Tetrahydronaphthyridine, benzoxazine, aza-benzoxazine and related bicyclic compounds for inhibition of RORgamma activity and the treatment of disease

ABSTRACT

The invention provides certain bicylic heterocyclic compounds of the Formula (I) or pharmaceutically acceptable salts thereof, wherein X 1 , X 2 , R 1 , R 2 , R 3 , R4, and Cy are as defined herein. The invention also provides pharmaceutical compositions comprising such compounds of the Formula (I) or pharmaceutically acceptable salts thereof, and methods of using the compounds of the Formula (I) or pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising the same for treating diseases or conditions mediated by RORgammaT.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is the national stage of International (PCT) PatentApplication Serial No. PCT/US2014/071671, filed Dec. 19, 2014 whichclaims the benefit of and priority to U.S. Provisional PatentApplication Ser. No. 61/919,120, filed Dec. 20, 2013, the contents ofeach of which are hereby incorporated by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to certain bicyclic heterocyclic compoundsof the Formula (I) (also referred to herein as the “compounds of theFormula (I)” or “compounds of Formula (I)”) which are antagonists of aThymocyte/T cell specific variant of Retinoic Acid Receptor-relatedOrphan Receptor (ROR), RORgammaT. The present invention also providescompositions comprising such compounds, and methods of using suchcompounds for treating conditions or disorders associated withinappropriate RORgammaT activity, in particular in the treatment andprevention of disease states mediated by RORgammaT. Such disease statesmay include immune and inflammatory disorders such as rheumatoidarthritis, psoriasis, multiple sclerosis, inflammatory bowel disease,and asthma.

BACKGROUND OF THE INVENTION

Upon activation by antigen-presenting cells naïve T helper cells undergoclonal expansion and will ultimately differentiate into cytokinesecreting effector T cells, such as Th1 and Th2 subtypes. A third anddistinct effector subset has been identified, which plays a key role inproviding immunity to bacteria and fungi at mucosal surfaces (Kasteleinet al., Annu. Rev. Immunol. 25: 221-242, 2007). This effector T helpercell subset can be distinguished based on its ability to produce largequantities of IL-17/F, IL-21 and IL-22, and is named Th17 (Miossec etal., New Eng. J. Med. 361: 888-898, 2009).

Different T helper subsets are characterized by the expression oflineage specific master transcription factors. Th1 and Th2 effectorcells express Tbet and GATA3, respectively. A Thymocyte/T cell specificvariant of Retinoic Acid Receptor-related Orphan Receptor (ROR),RORgammaT, is highly expressed in Th17 cells (He et al., Immunity 9:797-806, 1998). RORgammaT belongs to the nuclear hormone receptorsuperfamily (Hirose et al., Biochem. Biophys. Res. Comm. 205: 1976-1983,1994). RORgammaT is a truncated form of RORgamma, lacking the firstN-terminal 21 amino acids and is, in contrast to RORgamma which isexpressed in multiple tissues (heart, brain, kidney, lung, liver, andmuscle), exclusively expressed in cells of the lymphoid lineage andembryonic lymphoid tissue inducers (Sun et al., Science 288: 2369-2372,2000; Eberl et al., Nat Immunol. 5: 64-73, 2004).

Studies using heterozygous knock-in mice replacing the RORgammaT openreading frame with GFP (green fluorescent protein) revealed aconstitutive expression of GFP in approximately 10% of the CD4+ T cellsin the small intestinal lamina propria (LP), co-expressing the Th17cytokines IL-17/F and IL-22 (Ivanov et al., Cell 126: 1121-1133, 2006).In mice deficient for RORgammaT, the number of Th17 cells was markedlydecreased in the LP; and in vitro stimulation of CD4+ T cells under Th17polarizing conditions resulted in a drastic decrease of IL-17expression. These results were further substantiated via forcedexpression of RORgammaT in naïve CD4+ T cells, which resulted in aninduction of IL-17/F and IL-22 (Ivanov et al., Cell 126: 1121-1133,2006). The foregoing studies demonstrate the importance of RORgammaT indifferentiation and stabilization of the Th17 lineage. In addition, aROR family member, RORalpha, has been demonstrated to be involved inTh17 differentiation and stabilization (Yang et al., Immunity 28: 29-39,2008).

Recently, RORgammaT was shown to play a crucial role in non-Th17lymphoid cells. In these studies, RORgammaT was critically important ininnate lymphoid cells expressing Thy1, SCA-1, and IL-23R proteins.Genetic disruption of RORgamma in a mouse colitis model dependent onthese innate lymphoid cells prevented colitis development (Buonocore etal., Nature 464: 1371-1375, 2010). In addition, RORgammaT was shown toplay a crucial role in other non-Th17 cells, such as mast cells (Hueberet al., J. Immunol. 184: 3336-3340, 2010). Finally, RORgammaT expressionand secretion of Th17-type of cytokines was reported for Lymphoid TissueInducer cells, NK T-cells, NK cells (Eberl et al., Nat. Immunol. 5:64-73, 2004) and gamma-delta T-cells (Sutton et al., Immunity 31:331-341, 2009; Louten et al., J. Allergy Clin. Immunol. 123: 1004-1011,2009), suggesting an important function for RORgammaT in these subtypesof cells.

Based on the role of IL-17 producing cells (either Th17 or non-Th17cells) RORgammaT has been identified as a key mediator in thepathogenesis of several diseases (Louten et al., J. Allergy Clin.Immunol. 123: 1004-1011, 2009; Annunziato et al., Nat. Rev. Rheumatol.5: 325-331, 2009). This was confirmed using several disease modelsrepresentative of autoimmune diseases. Genetic ablation of the RORgammagene in mice prevented the development of experimental autoimmunediseases, such as experimental autoimmune encephalomyelitis (EAE) andcolitis (Ivanov et al., Cell 126:1121-33, 2006; Buonocore et al., Nature464: 1371-1375, 2010).

With RORgammaT being a critical mediator in Th17-cells and non-Th17cells, antagonism of the transcriptional activity of RORgammaT isexpected to have a beneficial effect on autoimmune diseases, such as butnot limited to rheumatoid arthritis, psoriasis, multiple sclerosis,inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis),and asthma (Annunziato et al., Nat. Rev. Rheumatol. 5: 325-331, 2009;Louten et al., J. Allergy Clin. Immunol. 123: 1004-1011, 2009).Antagonism of RORgammaT may also be beneficial in other diseases thatare characterized by increased levels of Th17 cells and/or elevatedlevels of Th17 hallmark cytokines such as IL-17, IL-22 and IL-23.Examples of such diseases are Kawasaki Disease (Jia et al., Clin. Exp.Immunol. 162: 131-137, 2010) and Hashimoto's thyroiditis (Figueroa-Vegaet al., J. Clin. Endocrinol. Metab. 95: 953-62, 2010). Another exampleincludes infectious diseases, such as but not limited to mucosalleishmaniasis (Boaventura et al., Eur. J. Immunol. 40: 2830-2836, 2010).In each of the above examples the inhibition may be enhanced bysimultaneous inhibition of RORalpha.

Compounds modulating RORgammaT have been reported. Examples of agonistsinclude T0901317 and SR1078 (Wang et al., ACS Chem. Biol. 5:1029-1034,2010). In addition, antagonists have been reported such as 7-oxygenatedsterols (Wang et al., J. Biol. Chem. 285: 5013-5025, 2010) and thecompounds described in EP 2181710 A1.

Numerous immune and inflammatory disorders continue to afflict millionsof patients worldwide. Although significant advances have been made intreating these disorders, current therapies do not provide satisfactoryresults for all patients due to, for example, detrimental side effectsor insufficient efficacy. One exemplary immune disorder in need ofbetter therapy is psoriasis. Various therapeutics have been developed inan attempt to treat psoriasis. However, the traditional therapies forpsoriasis often have toxic adverse effects. An exemplary inflammatorydisorder in need of better treatment is rheumatoid arthritis. Numeroustherapeutics have been developed in an attempt to treat this disorder.However, some patients develop resistance to current therapies.

Accordingly, a need exists for improved treatments for immune disordersand inflammatory disorders. The present invention addresses this needand provides other related advantages.

SUMMARY OF THE INVENTION

The present invention provides compounds that alter the interaction ofcoregulator proteins with RORgammaT and thereby antagonizeRORgammaT-mediated transcriptional activity; pharmaceutical compositionscomprising such compounds and pharmaceutically acceptable excipients;and use of such compounds or such pharmaceutical compositions for thetreatment of RORgammaT-mediated diseases or conditions, in particularautoimmune diseases and inflammatory diseases.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The terms used herein have their ordinary meaning and the meaning ofsuch terms is independent at each occurrence thereof. Thatnotwithstanding and except where stated otherwise, the followingdefinitions apply throughout the specification and claims. Chemicalnames, common names, and chemical structures may be used interchangeablyto describe the same structure. If a chemical compound is referred tousing both a chemical structure and a chemical name, and an ambiguityexists between the structure and the name, the structure predominates.These definitions apply regardless of whether a term is used by itselfor in combination with other terms, unless otherwise indicated. Hence,the definition of “alkyl” applies to “alkyl” as well as the “alkyl”portions of “hydroxyalkyl,” “fluoroalkyl,” “—O-alkyl,” etc.

As used herein, and throughout this disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

A “patient” is a human or non-human mammal. In one embodiment, a patientis a human. In another embodiment, a patient is a chimpanzee.

The term “therapeutically effective amount” as used herein refers to anamount of the compound of Formula (I) and/or an additional therapeuticagent, or a composition thereof that is effective in producing thedesired therapeutic, ameliorative, inhibitory, or preventative effectwhen administered to a patient suffering from a disease or conditionmediated by RORgammaT. In the combination therapies of the presentinvention, a therapeutically effective amount can refer to eachindividual agent or to the combination as a whole, wherein the amountsof all agents administered are together effective, but wherein thecomponent agent of the combination may not be present individually in aneffective amount.

The term “preventing,” as used herein with respect to an inflammatorydisease or disorder, refers to reducing the likelihood of an autoimmuneor inflammatory disease or disorder.

The term “alkyl,” as used herein, refers to an aliphatic hydrocarbongroup having one of its hydrogen atoms replaced with a bond having thespecified number of carbon atoms. In different embodiments, an alkylgroup contains from 1 to 6 carbon atoms (C₁-C₆ alkyl) or from 1 to 3carbon atoms (C₁-C₃ alkyl). Non-limiting examples of alkyl groupsinclude methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl,isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl,and neohexyl. In one embodiment, an alkyl group is linear. In anotherembodiment, an alkyl group is branched.

The term “fluoroalkyl,” as used herein, refers to an alkyl group asdefined above, wherein one or more of the alkyl group's hydrogen atomshave been replaced with a fluorine. In one embodiment, a fluoroalkylgroup has from 1 to 6 carbon atoms. In another embodiment, a fluoroalkylgroup has from 1 to 3 carbon atoms. In another embodiment, a fluoroalkylgroup is substituted with from 1 to 3 fluorine atoms. Non-limitingexamples of fluoroalkyl groups include —CH₂F, —CHF₂, and —CF₃. The term“C₁-C₃ fluoroalkyl” refers to a fluoroalkyl group having from 1 to 3carbon atoms.

The term “alkylene,” as used herein, refers to an alkyl group, asdefined above, wherein one of the alkyl group's hydrogen atoms has beenreplaced with a bond. Non-limiting examples of alkylene groups include—CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, —CH(CH₃)CH₂CH₂—,—CH(CH₃)—, and —CH₂CH(CH₃)CH₂—. In one embodiment, an alkylene group hasfrom 1 to about 6 carbon atoms (C₁-C₆ alkylene). In another embodiment,an alkylene group has from 1 to 3 carbon atoms (C₁-C₃ alkylene). Inanother embodiment, an alkylene group is branched. In anotherembodiment, an alkylene group is linear. In one embodiment, an alkylenegroup is —CH₂—. The term “C₁-C₃ alkylene” refers to an alkylene grouphaving from 1 to 3 carbon atoms. Unless otherwise indicated, an alkylenegroup is unsubstituted.

The term “alkenyl,” as used herein, refers to an aliphatic hydrocarbongroup containing at least one carbon-carbon double bond and having oneof its hydrogen atoms replaced with a bond. An alkenyl group may bestraight or branched and contain from about 2 to about 15 carbon atoms.In one embodiment, an alkenyl group contains from about 2 to 4 carbonatoms. Non-limiting examples of alkenyl groups include ethenyl,propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl, anddecenyl. The term “C₂-C₆ alkenyl” refers to an alkenyl group having from2 to 6 carbon atoms. The term “C₂-C₄ alkenyl” refers to an alkenyl grouphaving from 2 to 4 carbon atoms. Unless otherwise indicated, an alkenylgroup is unsubstituted.

The term “alkoxy,” as used herein, refers to an —O-alkyl group, whereinan alkyl group is as defined above. Non-limiting examples of alkoxygroups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, andtert-butoxy. An alkoxy group is bonded via its oxygen atom to the restof the molecule.

The term “aryl,” as used herein, refers to an aromatic monocyclic ormulticyclic ring system comprising from about 6 to about 14 carbonatoms. In one embodiment, an aryl group contains from about 6 to 10carbon atoms (C₆-C₁₀ aryl). In another embodiment an aryl group isphenyl. Non-limiting examples of aryl groups include phenyl andnaphthyl.

The term “carbocycle,” as used herein, refers to a fully saturated,partially unsaturated, or an aromatic monocyclic or multicyclic ringsystem comprising from about 6 to 14 carbon atoms. In one embodiment, anaryl group contains from 3 to 10 carbon atoms (C₃-C₁₀ carbocycle).Non-limiting examples of carbocyclic groups include cycloalkyl and arylgroups, as defined herein. In specific embodiments, the carbocyclicgroups are selected from cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, phenyl, indanyl, naphthyl, and tetrahydronaphthyl.

The term “cycloalkyl,” as used herein, refers to a saturated ringcontaining the specified number of ring carbon atoms, and no heteroatom.In a like manner the term “C₃-C₆ cycloalkyl” refers to a saturated ringhaving from 3 to 6 ring carbon atoms. Non-limiting examples ofmonocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl.

The term “halo,” as used herein, means —F, —Cl, —Br or —I. In oneembodiment, a halo group is —F or —Cl. In another embodiment, a halogroup is —F.

“Heterocyclyl” refers to a 4-, 5-, 6-, or 7-membered monocyclic ring or8-, 9-, or 10-membered bicyclic ring, or 13- or 14-membered tricyclicring, saturated, unsaturated or aromatic, containing 1, 2, 3, or 4heteroatoms selected from O, N, or S, and the heterocyclyl mayoptionally be substituted with one to four substituents. The nitrogen orsulfur atom of the heterocyclyl can be optionally oxidized to thecorresponding N-oxide, S-oxide, or S,S-dioxide. A heterocyclyl group canbe joined to the rest of the molecule via a ring carbon or ring nitrogenatom. Representative heterocyclyls are as follows: azetidinyl,pyrrolidinyl, pyrrolyl, tetrahydrofuran, imidazolyl, imidazolinyl,1,3-oxazolidinyl, 1,2-oxazolidinyl, isoxazolyl, 1,2,4-oxadiazolyl,1,3,4-oxadiazolyl, tetrahydropyranyl, piperidinyl, piperazinyl,morpholinyl, pyrimidinyl, pyrrolopyrazine, pyrrolopyridine, and indolyl.

The term “substituted” means that one or more hydrogens on thedesignated atom/atoms is/are replaced with a selection from theindicated group, provided that the designated atom's normal valencyunder the existing circumstances is not exceeded, and that thesubstitution results in a stable compound. Combinations of substituentsand/or variables are permissible only if such combinations result instable compounds. By “stable compound” or “stable structure” is meant acompound that is sufficiently robust to survive isolation from areaction mixture to a useful degree of purity, and formulation into anefficacious therapeutic agent.

When any substituent or variable occurs more than one time in anyconstituent or in the compound of Formula (I), its definition on eachoccurrence is independent of its definition at every other occurrence,unless otherwise indicated.

When an integer defining the presence of a certain number of atoms in agroup is equal to zero, it means that the atoms adjacent thereto areconnected directly by a bond; for example, in the structure

wherein s is an integer equal to zero, 1 or 2, the structure is

when s is zero; or it means that the indicated atom is absent; forexample, —S(O)₀— means —S—.

The term “in purified form,” as used herein, refers to the physicalstate of a compound after the compound has been isolated through asynthetic process (e.g., from a reaction mixture), from a naturalsource, or a combination thereof. The term “in purified form” alsorefers to the physical state of a compound after the compound has beenobtained from a purification process or processes described herein orwell-known to the skilled artisan (e.g., chromatography,recrystallization, and the like), in sufficient purity to becharacterizable by standard analytical techniques described herein orwell-known to the skilled artisan.

It should also be noted that any carbon as well as heteroatom withunsatisfied valences in the text, schemes, examples, and tables hereinis assumed to have the sufficient number of hydrogen atom(s) to satisfythe valences.

One or more compounds of the invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms. “Solvate” means a physicalassociation of a compound of this invention with one or more solventmolecules. This physical association involves various degrees of ionicand covalent bonding, including hydrogen bonding. In certain instancesthe solvate will be capable of isolation, for example when one or moresolvent molecules are incorporated in the crystal lattice of thecrystalline solid. “Solvate” encompasses both solution-phase andisolatable solvates. Non-limiting examples of suitable solvates includeethanolates, methanolates, and the like. “Hydrate” is a solvate whereinthe solvent molecule is H₂O.

The compounds of Formula (I) may contain one or more stereogenic centersand can thus occur as racemates, racemic mixtures, single enantiomers,diastereomeric mixtures, and individual diastereomers. Additionalasymmetric centers may be present depending upon the nature of thevarious substituents on the molecule. Each such asymmetric center willindependently produce two optical isomers and it is intended that all ofthe possible optical isomers and diastereomers in mixtures and as pureor partially purified compounds are included within the ambit of thisinvention. Any formulas, structures, or names of compounds described inthis specification that do not specify a particular stereochemistry aremeant to encompass any and all existing isomers as described above andmixtures thereof in any proportion. When stereochemistry is specified,the invention is meant to encompass that particular isomer in pure formor as part of a mixture with other isomers in any proportion.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers, and converting (e.g., hydrolyzing) theindividual diastereomers to the corresponding pure enantiomers. Also,some of the compounds of Formula (I) may be atropisomers (e.g.,substituted biaryls) and are considered as part of this invention.Enantiomers can also be separated by use of chiral HPLC column.

It is also possible that the compounds of Formula (I) may exist indifferent tautomeric forms, and all such forms are embraced within thescope of the invention.

All stereoisomers (for example, geometric isomers, optical isomers, andthe like) of the present compounds (including stereoisomers of salts andsolvates of the present compounds as well as stereoisomers of salts,solvates, and esters of prodrugs of the present compounds), such asthose that may exist due to asymmetric carbons on various substituents,including enantiomeric forms (which may exist even in the absence ofasymmetric carbons), rotameric forms, atropisomers, and diastereomericforms, are contemplated within the scope of this invention. Individualstereoisomers of the compounds of the invention may, for example, besubstantially free of other isomers, or may be admixed, for example, asracemates or with all other, or other selected, stereoisomers. Thechiral centers of the present invention can have the S or Rconfiguration as defined by the IUPAC 1974 Recommendations.

The compounds of Formula (I) can form salts which are also within thescope of this invention. Reference to a compound of Formula (I) hereinis understood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s),” as employed herein, denotes acidic saltsformed with inorganic and/or organic acids, as well as basic saltsformed with inorganic and/or organic bases. In addition, when a compoundof Formula (I) contains both a basic moiety, such as but not limited toa pyridine or imidazole, and an acidic moiety, such as but not limitedto a carboxylic acid, zwitterions (“inner salts”) may be formed and areincluded within the term “salt(s)” as used herein. Such acidic and basicsalts used within the scope of the invention are pharmaceuticallyacceptable (i.e., non-toxic, physiologically acceptable) salts. Salts ofthe compounds of Formula (I) may be formed, for example, by reacting acompound of Formula (I) with an amount of acid or base, such as anequivalent amount, in a medium such as one in which the saltprecipitates or in an aqueous medium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, fumarates, hydrochlorides,hydrobromides, hydroiodides, lactates, maleates, methanesulfonates,naphthalenesulfonates, nitrates, oxalates, phosphates, propionates,salicylates, succinates, sulfates, tartarates, thiocyanates,toluenesulfonates (also known as tosylates), and the like. Additionally,acids that are generally considered suitable for the formation ofpharmaceutically useful salts from basic pharmaceutical compounds arediscussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook ofPharmaceutical Salts. Properties, Selection and Use. (2002) Zurich:Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977)66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al, The Practice of Medicinal Chemistry (1996),Academic Press, New York; and in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website). These disclosuresare incorporated herein by reference.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as dicyclohexylamines, t-butyl amines, and saltswith amino acids such as arginine, lysine, and the like. Basicnitrogen-containing groups may be quaternized with agents such as loweralkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides, andiodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g., decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g., benzyl andphenethyl bromides), and others.

The present invention further includes the compounds of Formula (I) inall their isolated forms. For example, the above-identified compoundsare intended to encompass all forms of the compounds, such as anysolvates, hydrates, stereoisomers, and tautomers thereof.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product that results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

In the compounds of generic Formula (I), the atoms may exhibit theirnatural isotopic abundances, or one or more of the atoms may beartificially enriched in a particular isotope having the same atomicnumber, but an atomic mass or mass number different from the atomic massor mass number predominantly found in nature. The present invention ismeant to include all suitable isotopic variations of the compounds ofgeneric Formula (I). For example, different isotopic forms of hydrogen(H) include protium (¹H) and deuterium (²H). Protium is the predominanthydrogen isotope found in nature. Enriching for deuterium may affordcertain therapeutic advantages, such as increasing in vivo half-life orreducing dosage requirements, or may provide a compound useful as astandard for characterization of biological samples. In light of thepresent disclosure, isotopically-enriched compounds within genericFormula (I) can be prepared without undue experimentation byconventional techniques well known to those skilled in the art or byprocesses analogous to those described in the examples herein usingappropriate isotopically-enriched reagents and/or intermediates.

Compounds of the Invention

The present invention provides a compound of Formula (I) or apharmaceutically acceptable salt thereof, wherein X¹, X², R¹, R², R³,R⁴, and Cy are as defined below. Described below are embodiments of thecompound of Formula (I). The compound of the Formula (IA), shown below,is an embodiment of the compound of Formula (I).

In embodiment no. 1, the invention provides a compound of Formula (I),

or a pharmaceutically acceptable salt thereof, wherein:X¹ is C(R²) or N;X² is O, S, S(O), S(O)₂, CH₂, or C(O);R¹ is H, C₁-C₃ alkyl, or C₁-C₃ alkyl substituted by hydroxy;R² is H, halo, or C₁-C₃ alkyl;R³ is selected from the group consisting of:

(a.) H;

(b.) C₁-C₆ alkyl;

(c.) —(C(R^(a))₂)_(n1)OH;

(d.) —(C(R^(a))₂)_(n1)N(R^(b))₂;

(e.) —(C(R^(a))₂)_(n1)N(H)C(O)N(R^(b))₂;

(f.) —(C(R^(a))₂)_(n1)N(H)C(O)R^(d);

(g.) —(C(R^(a))₂)_(n1)N(H)S(O)₂N(R^(b))₂;

(h.) —(C(R^(a))₂)_(n1)N(H)S(O)₂R^(d);

(i.) —(C(R^(a))₂)_(n1)CO₂R^(c);

(j.) —(C(R^(a))₂)_(n2)C(O)N(R^(b))₂;

(k.) —(C(R^(a))₂)_(n1)S(O)₂N(R^(b))₂;

(l.) —(C(R^(a))₂)_(n2)N(H)C(O)OR^(d);

(m.) —(C(R^(a))₂)_(n2)C(O)N(H)S(O)₂R^(d);

(n.) —(C(R^(a))₂)_(n1)N(H)S(O)₂OR^(d);

(o.) —(C(R^(a))₂)_(n1)S(O)_(n3)R^(d);

(p.) —(C(R^(a))₂)_(n2)C(O)N(H)OR^(d);

(q.) —(C(R^(a))₂)_(n1)CN;

(r.) —C^(H) or —(C(R^(a))₂)_(n1)—C^(H);

(s.) —C(R^(a))₂O—C^(C);

(t.) —C(O)CF₃;

(u.) —OH, with the proviso that R³ is —OH only when X² is CH₂; and

(v.) —N(R^(b))₂, with the proviso that R³ is —N(R^(b))₂ only when X² isCH₂;

-   -   each R^(a) is independently H, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl,        or C₃-C₆ cycloalkyl, or alternatively two R^(a) when bonded to a        common carbon atom may together with the common carbon atom form        a cyclopropyl ring;    -   each R^(b) is independently:        -   (i.) H;        -   (ii.) C₁-C₆ alkyl, wherein said C₁-C₆ alkyl is unsubstituted            or independently substituted by 1 to 3 fluoro, or hydroxyl;        -   (iii.) —(CH₂)_(n3)CO₂R^(e); or        -   (iv.) —C^(C) or —CH₂—C^(C); or        -   alternatively, two R^(b) together with the N atom to which            they are attached form a 5- to 9-membered heterocyclyl,            wherein said heterocyclyl is a saturated, partially            saturated, or aromatic ring system containing 0, 1, or 2            additional heteroatoms independently selected from the group            consisting of N, O, S, and S(O)₂; wherein said heterocyclyl            is unsubstituted or substituted by 1 to 4 moieties            independently selected from the group consisting of C₁-C₆            alkyl, C₁-C₃ alkoxy, fluoro, hydroxyl, oxo, cyano, amino,            C₁-C₃ alkylamino, and C₁-C₃ dialkylamino;    -   R^(c) is        -   (i.) H;        -   (ii.) C₁-C₆ alkyl, wherein said C₁-C₆ alkyl is unsubstituted            or independently substituted by 1 to 3 fluoro or hydroxy; or        -   (iii.) —C^(C) or CH₂—C^(C);    -   R^(d) is        -   (i.) C₁-C₆ alkyl, wherein said C₁-C₆ alkyl is unsubstituted            or independently substituted by 1 to 3 fluoro or hydroxy;        -   (ii). —C(O)N(R^(f))₂; or        -   (iii.) —C^(C) or CH₂—C^(C);    -   R^(e) is H or C₁-C₃ alkyl;    -   R^(f) is H or C₁-C₃ alkyl;    -   ring C^(H) is        -   (i.) C₃-C₆ cycloalkyl;        -   (ii.) phenyl; or        -   (iii.) a 4- to 9-membered mono- or bicyclic heterocyclyl,            wherein said heterocyclyl is a saturated, partially            saturated, or aromatic ring system containing 1 to 4            heteroatoms independently selected from the group consisting            of N, O, S, and S(O)₂;        -   wherein ring C^(H) is unsubstituted or independently            substituted by 1 to 4 C₁-C₆ alkyl, C₁-C₃ alkoxy, halo,            hydroxyl, oxo, cyano, amino, C₁-C₃ alkylamino, or C₁-C₃            dialkylamino;    -   ring C^(C) is        -   (i.) C₃-C₆ cycloalkyl;        -   (ii.) phenyl; or        -   (iii.) a heterocyclyl of the formula

-   -   -    wherein said heterocyclyl is a 5- to 9-membered            heterocyclyl, wherein said heterocyclyl is a saturated,            partially saturated, or aromatic ring system that contains            1, 2, or 3 heteroatoms independently selected from the group            consisting of N, O, S, and S(O)₂;        -   wherein ring C^(C) is unsubstituted or independently            substituted by 1 to 4 C₁-C₆ alkyl, C₁-C₃ alkoxy, halo,            hydroxyl, oxo, cyano, amino, C₁-C₃ alkylamino, or C₁-C₃            dialkylamino;

the subscript n1 is 1, 2, or 3;

the subscript n2 is 0, 1, 2, or 3;

the subscript n3 is 1 or 2;

R⁴ is

-   -   (a.) C₁-C₈ alkyl, wherein said C₁-C₈ alkyl of R⁴ is        unsubstituted or independently substituted by 1 to 6 halo, C₁-C₃        alkoxy, hydroxy, cyano, trimethylsilyl, or methylsulfonyl;    -   (b.) C₂-C₈ alkenyl, wherein said C₂-C₈ alkenyl of R⁴ is        unsubstituted or independently substituted by 1 to 6 fluoro or        cyano; or    -   (c.) a group of the formula -M-R^(CH);        -   M is            -   (i.) a bond; or            -   (ii.) C₁-C₆ alkylene, wherein said C₁-C₆ alkylene of M                is unsubstituted or substituted by 1 to 6 fluoro;        -   R^(CH) is a ring selected from the group consisting of            -   (i.) C₃-C₉ mono- or bicycloalkyl;            -   (ii.) phenyl; and            -   (iii.) a 3- to 6-membered heterocyclyl, wherein said                heterocyclyl of R^(CH) is a saturated, partially                saturated or aromatic ring system containing 1 to 2                heteroatoms independently selected from the group                consisting of N, O, and S;            -   wherein R^(CH) is unsubstituted or independently                substituted by 1 to 4 halo, C₁-C₃ alkyl, C₁-C₃                trifluoroalkyl, cyano, C₁-C₄ alkylcarbonylamino, or oxo;                Cy is    -   (a.) phenyl;    -   (b.) C₃-C₆ cycloalkyl;    -   (c.) a 5- to 9-membered mono- or bicyclic heterocyclyl, wherein        said heterocyclyl of Cy is a saturated, partially saturated, or        aromatic ring system containing 1 to 3 heteroatoms independently        selected from the group consisting of N, O, S and S(O)₂; or    -   wherein Cy is unsubstituted or independently substituted by 1 to        4 R^(k) moieties selected from the group consisting of:        -   (i.) C₁-C₆ alkyl, wherein said C₁-C₆ alkyl is unsubstituted            or independently substituted by 1 to 3 hydroxy or fluoro;        -   (ii.) C₁-C₆ alkoxy, wherein said C₁-C₆ alkoxy is            unsubstituted or independently substituted by 1 to 3 fluoro,            hydroxy, amino, (C₁-C₃ alkyl)amino, di(C₁-C₃ alkyl)amino,            methoxy, or phenyl;        -   (iii.) —N(R^(e1))₂;        -   (iv.) —O(CH₂)_(n4)C(O)N(R^(e1))₂;        -   (v.) —O(CH₂)_(n5)CO₂R^(e1);        -   (vi.) hydroxyl;        -   (vii.) oxo;        -   (viii.) halo;        -   (ix.) C₁-C₃ alkylsulfonyl;        -   (x.) cyano;        -   (xi.) oxetanyl; and        -   (xii.) cyclopropyl;    -   or alternatively, two R^(k) moieties, when substituted on        adjacent ring atoms of Cy, form a second ring, wherein said        second ring is a 5- to 7-membered saturated, partially        saturated, or aromatic ring system that contains 0, 1, or 2        heteroatoms independently selected from the group consisting of        N, O, and S; wherein said second ring is unsubstituted or        substituted by 1 to 3 R^(k) moieties independently selected from        (i)-(xi);        -   each R^(e1) is independently H or C₁-C₃ alkyl;        -   the subscript n4 is 1, 2, or 3;        -   the subscript n5 is 1, 2, or 3;

In embodiment no. 2, the invention provides a compound of Formula (I),wherein

(a.) X¹ is C(R²) and X² is O;

(b.) X¹ is N and X² is O; or

(c.) X¹ is N and X² is CH₂; and

the remaining variables are as described in embodiment no. 1.

In embodiment no. 3, the invention provides a compound of Formula (I),wherein

X¹ is C(R²) and X² is O. and

the remaining variables are as described in embodiment no. 1.

In embodiment no. 4, the invention provides a compound of Formula (I),wherein R³ is other than —C(R^(a))₂N(H)C(O)R^(d),—C(R^(a))₂N(H)S(O)₂R^(d), or —(C(R^(a))₂)₂CO₂R^(c), and the remainingvariables are as described in embodiment no. 1.

In embodiment no. 5, the invention provides a compound of Formula (I),wherein R³ is a group of the formula —(C(R^(a))₂)_(n1)N(H)S(O)₂N(R^(b))₂and the remaining variables are as described in embodiment no. 1.

In embodiment no. 6, the invention provides a compound of Formula (I),wherein R³ is as described in embodiment no. 5, the subscript n1 is 1,and the remaining variables are as described in embodiment no. 1.

In embodiment no. 7, the invention provides a compound of Formula (I),wherein R³ is as described in embodiment no. 5, the subscript n1 is 1,and each R^(b) is independently:

-   -   (i.) H;    -   (ii.) C₁-C₄ alkyl, wherein said C₁-C₄ alkyl is unsubstituted or        substituted by 1 to 3 fluoro;    -   (iii.) —C^(C);    -   alternatively, two R^(b) together with the N atom to which they        are attached form a 5- to 6-membered heterocyclyl, wherein said        heterocyclyl is selected from the group consisting of        pyrrolidinyl, piperidinyl, and morpholinyl; wherein said        heterocyclyl is unsubstituted or substituted by 1 to 2 moieties        independently selected from the group consisting of C₁-C₆ alkyl,        C₁-C₃ alkoxy, fluoro, hydroxyl, oxo, cyano, amino, C₁-C₃        alkylamino, and C₁-C₃ dialkylamino; and    -   ring C^(C) is C₃-C₆ cycloalkyl;        -   wherein ring C^(C) is unsubstituted or independently            substituted by 1 to 2 C₁-C₆ alkyl, C₁-C₃ alkoxy, halo,            hydroxyl, oxo, cyano, amino, C₁-C₃ alkylamino, or C₁-C₃            dialkylamino;            and the remaining variables are as described in embodiment            no. 1.

In embodiment no. 8, the invention provides a compound of Formula (I),wherein Cy is a group of the formula

wherein the subscript s is 0, 1, 2, or 3; and the remaining variablesare as described in embodiment no. 1.

In embodiment no. 9, the invention provides a compound of Formula (I),wherein Cy is a group of the formula

whereinthe subscript p is 1 or 2;the subscript s is 0, 1, or 2; and the remaining variables are asdescribed in embodiment no. 1.

In embodiment no. 10, the invention provides a compound of Formula (I),wherein Cy is

whereinR^(k1) is C₁-C₆ alkyl or CH₂CH₂OH;R^(k2) is C₁-C₃ alkyl or CHF₂; and the remaining variables are asdescribed in embodiment no. 1.

In embodiment no. 11, the invention provides a compound of Formula (I),wherein Cy is

wherein R^(k2) is C₁-C₃ alkyl or CHF₂; and the remaining variables areas described in embodiment no. 1.

In embodiment no. 12, the invention provides a compound of Formula (I),wherein Cy is a group of the formula:

whereinR^(k1) is C₁-C₆ alkyl or CH₂CH₂OH; and the remaining variables are asdescribed in embodiment no. 1.

In embodiment no. 13, the invention provides a compound of Formula (I),wherein

wherein R^(k3) is C₁-C₃ alkyl or C₁-C₃ fluoroalkyl; and the remainingvariables are as described in embodiment no. 1.

In embodiment no. 14, the invention provides a compound of Formula (I),wherein R⁴ is a group of the formula

and the remaining variables are as described in embodiment no. 1.

In embodiment no. 15, the invention provides a compound of Formula (I),wherein R¹ is H or methyl, and the remaining variables are as describedin embodiment no. 1.

In embodiment no. 16, the invention provides a compound of Formula (I),wherein:

X¹ and X² are as described in embodiment no. 2;

R¹ is as described in embodiment no. 15;

R² is H;

R³ is as described in embodiment no. 4;

R⁴ is as described in embodiment no. 14; and

Cy is as described in any one of embodiments nos. 8-13.

In embodiment no. 17, the invention provides a compound of Formula (I),wherein:

X¹ and X² are as described in embodiment no. 2;

R¹ is as described in embodiment no. 15;

R² is H;

R³ is as described in embodiment no. 6;

R⁴ is as described in embodiment no. 14; and

Cy is as described in any one of embodiments nos. 8-13.

In embodiment no. 18, the invention provides a compound of Formula (I),wherein R^(b) is as described in embodiment no. 7; and R¹, R², R³, R⁴,and Cy are as described in embodiment no. 17.

In embodiment no. 19, the invention provides a compound of Formula (I),wherein X¹ and X² are as described in embodiment no. 3, and R¹, R², R³,R⁴, and Cy are as described in embodiment no. 16.

In embodiment no. 20, the invention provides a compound of Formula (I),wherein X¹ and X² are as described in embodiment no. 3, and R¹, R², R³,R⁴, and Cy are as described in embodiment no. 17.

In embodiment no. 21, the invention provides a compound of Formula (I),wherein X¹ and X² are as described in embodiment no. 3,

R³ is as described in embodiment no. 7; and

R¹, R², R⁴, and Cy are as described in embodiment no. 17.

In embodiment no. 22, the invention provides a compound of Formula (I),wherein Cy is as described in embodiment no. 8;

X¹ and X² are as described in embodiment no. 3; and

R¹, R², R³, and R⁴ are as described in embodiment no. 17.

In embodiment no. 23, the invention provides a compound as set forth inany one of embodiment nos. 1-15, wherein R² is H.

In embodiment no. 24, the invention provides a compound as set forth inany one of embodiment nos. 1-23, wherein the compound of Formula (I) hasthe Formula (IA):

In embodiment no. 25, the invention provides a compound of the Formula(I) wherein;

-   -   X¹ is C(H);    -   X² is CH₂;    -   R¹ is H;    -   R² is H;    -   R³ is:        -   (a.) H;        -   (b.) —CH₂N(H)C(O)CH₃; and        -   (c.) —(CH₂)₃CO₂H;    -   R⁴ is as described in embodiment no. 14;    -   Cy is phenyl, pyrazolyl, or pyridyl, wherein Cy is unsubstituted        or substituted by 1 or 2 R^(k) moieties selected from the group        consisting of C₁-C₃ alkyl, C₁-C₃ alkoxy, trifluoromethyl, halo,        and —CH₂CH₂OH.

In embodiment no. 26, the invention provides a compound of the Formula(I) wherein;

-   -   X¹ is N;    -   X² is CH₂;    -   R¹ is H or methyl;    -   R² is H;    -   R³ is:        -   (a.) H;        -   (b.) —N(H)C(O)O—(C₁-C₆ alkyl);        -   (c.) —CH₂OH;        -   (d.) —CH₂S(O)₂CH₂CH₃; or        -   (e.) a group of the formula

-   -   -    which is unsubstituted or substituted by oxo or hydroxyl;

    -   R⁴ is:        -   (a.) C₁-C₈ alkyl, wherein said C₁-C₈ alkyl of R4 is            unsubstituted or substituted by 1 to 3 fluoro; or        -   (b.) —CH₂-phenyl; and

    -   Cy is phenyl or pyrazolyl, wherein Cy is unsubstituted or        substituted by 1 or 2 R^(k) moieties selected from the group        consisting of C₁-C₃ alkyl, C₁-C₃ fluoroalkyl, cyano, and halo.

In embodiment no. 27, the invention provides a compound of the Formula(I) wherein;

-   -   X¹ is C(H);    -   X² is O;    -   R¹ is H;    -   R² is H;    -   R³ is:        -   (a.) —CH₂N(H)S(O)₂N(R^(b))₂; or        -   (b.) a group of the formula

-   -   R^(b) is as set forth in embodiment no. 1;    -   R⁴ is as described in embodiment no. 14;    -   Cy is phenyl or pyrazolyl, wherein Cy is unsubstituted or        substituted by 1 or 2 R^(k) moieties selected from the group        consisting of C₁-C₃ alkyl, C₁-C₃ alkoxy, trifluoromethyl, halo,        and —CH₂CH₂OH.

In embodiment no. 28, the invention provides a compound of the Formula(I) wherein;

-   -   X¹ is C(H);    -   X² is O;    -   R¹ is methyl;    -   R² is H;    -   R³ is:        -   (a.) H;        -   (b.) —C(H)(R^(a))N(H)C(O)OR^(d); or        -   (c.) —CH₂N(H)S(O)₂N(R^(b))₂;        -   R^(b) and R^(d) are as described in embodiment no. 1;    -   R⁴ is as described in embodiment no. 14; and    -   Cy is phenyl or pyrazolyl, wherein Cy is unsubstituted or        substituted by 1 or 2 R^(k) moieties selected from the group        consisting of C₁-C₃ alkyl, C₁-C₃ alkoxy, trifluoromethyl, halo,        and —CH₂CH₂OH.

In embodiment no. 29, the invention provides a compound of the Formula(I) wherein;

-   -   X¹ is C(H);    -   X² is O;    -   R¹ is H;    -   R² is H;    -   R³ is:        -   (a.) —CH₂N(H)C(O)N(R^(b))₂; or        -   (b.) —CH₂N(H)C(O)OR^(d);        -   R^(b) and R^(d) are as described in embodiment no. 1;    -   R⁴ is as described in embodiment no. 14; and    -   Cy is phenyl, pyrazolyl, or pyridyl, wherein Cy is unsubstituted        or substituted by 1 or 2 R^(k) moieties selected from the group        consisting of C₁-C₃ alkyl, C₁-C₃ alkoxy, trifluoromethyl, halo,        and —CH₂CH₂OH.

In embodiment no. 30, the compound is selected from any one of thecompounds described in Examples 1-121 (or a pharmaceutically acceptablesalt thereof).

In embodiment no. 31, the compound is selected from any one of thefollowing compounds (or a pharmaceutically acceptable salt thereof):

-   (R)-tert-butyl    (2-(hydroxymethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-tert-butyl    (4-((5-bromo-2-chloropyridin-3-yl)sulfonyl)-2-(hydroxymethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-4-((6-((tert-butoxycarbonyl)amino)-2-(hydroxymethyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)sulfonyl)-1-(difluoromethyl)-3-methyl-1H-pyrazol-2-e;-   [(R)-4-((3-chloro-benzenesulfonyl)-2-hydroxymethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamic    acid tert-butyl ester;-   (R)-tert-butyl    (4-((5-bromopyridin-3-yl)sulfonyl)-2-(hydroxymethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-tert-butyl    (2-(hydroxymethyl)-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-tert-butyl    (2-(hydroxymethyl)-4-((3-(methylsulfonyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-tert-butyl    (4-((2-chloro-5-methylpyridin-3-yl)sulfonyl)-2-(hydroxymethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-tert-butyl    (4-((3-cyanophenyl)sulfonyl)-2-(hydroxymethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-tert-butyl    (2-(hydroxymethyl)-4-((5-methyl-2-oxo-1,2-dihydropyridin-3-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-tert-butyl    (4-((4-fluorophenyl)sulfonyl)-2-(2-hydroxypropan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (4-((4-fluorophenyl)sulfonyl)-2-(2-hydroxypropan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R and S)-1,1,1-trifluoro-2-methylpropan-2-yl    4-(3,4-difluorophenylsulfonyl)-2-(2,2,2-trifluoroacetyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-ylcarbamate;-   (R and S)-1,1,1-trifluoro-2-methylpropan-2-yl    (4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2,2,2-trifluoroacetyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (2-(aminomethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (2-(((benzyloxy)carbonyl)aminomethyl)-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (4-((4-fluorophenyl)sulfonyl)-2-((3-(tetrahydro-2H-pyran-4-yl)ureido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(((benzyloxy)carbonyl)aminomethyl)-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (2-(((benzyloxy)carbonyl)aminomethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(((methoxy)carbonyl)aminomethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (2-((3-cyclopropylureido)methyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (2-((3-cyclobutylureido)methyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (2-((3-(tert-butyl)ureido)methyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (4-((4-fluorophenyl)sulfonyl)-2-((3-isopropylureido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-2-((3-(thiophen-3-yl)ureido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (2-((3-ethylureido)methyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (2-((3-cyclohexylureido)methyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-1,1,1-trifluoro-2-methylpropan-2-yl    (4-((3-chloro-4-fluorophenyl)sulfonyl)-2-((5-methyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (4-((4-fluorophenyl)sulfonyl)-2-(((N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (4-((4-fluorophenyl)sulfonyl)-2-((morpholine-4-sulfonamido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (2-(((N,N-diethylsulfamoyl)amino)methyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (2-(((N,N-dimethylsulfamoyl)amino)methyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-2-((piperidine-1-sulfonamido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-2-((pyrrolidine-1-sulfonamido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   1,1,1-trifluoro-2-methylpropan-2-yl    ((2S)-4-((4-fluorophenyl)sulfonyl)-2-((2-methylpiperidine-1-sulfonamido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   1,1,1-trifluoro-2-methylpropan-2-yl((2S)-2-((2,6-dimethylmorpholine-4-sulfonamido)methyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (4-((4-fluorophenyl)sulfonyl)-2-((4-methylpiperidine-1-sulfonamido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   1,1,1-trifluoro-2-methylpropan-2-yl((2S)-4-((4-fluorophenyl)sulfonyl)-2-((2-methylmorpholine-4-sulfonamido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (2-(((N-cyclopropyl-N-methylsulfamoyl)amino)methyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(((N-cyclopentyl-N-methylsulfamoyl)amino)methyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (4-((4-fluorophenyl)sulfonyl)-2-(((N-methyl-N-(2,2,2-trifluoroethyl)sulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (4-((3-chloro-4-fluorophenyl)sulfonyl)-2-(((N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (4-((3-chloro-4-fluorophenyl)sulfonyl)-2-((piperidine-1-sulfonamido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   1,1,1-trifluoro-2-methylpropan-2-yl((2S)-4-((3-chloro-4-fluorophenyl)sulfonyl)-2-(2-methylpiperidine-1-sulfonamido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   1,1,1-trifluoro-2-methylpropan-2-yl((2S)-4-((3-chloro-4-fluorophenyl)sulfonyl)-2-((2-methylmorpholine-4-sulfonamido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (4-((3-chloro-4-fluorophenyl)sulfonyl)-2-(((N-methyl-N-(2,2,2-trifluoroethyl)sulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (4-((3-chloro-4-fluorophenyl)sulfonyl)-2-(((N-isobutyl-N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   1,1,1-trifluoro-2-methylpropan-2-yl((2S)-4-((3-chloro-4-fluorophenyl)sulfonyl)-2-((3-methylpyrrolidine-1-sulfonamido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (4-((3-chloro-4-fluorophenyl)sulfonyl)-2-(((N-ethylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (4-((3-chloro-4-fluorophenyl)sulfonyl)-2-(((N-isopropylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (2-(((N-ethylsulfamoyl)amino)methyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-2-(((N-isopropylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (2-(((N-(tert-butyl)sulfamoyl)amino)methyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (4-((3,4-difluorophenyl)sulfonyl)-2-(((N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (4-((3-ethoxy-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(((N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (4-((1-ethyl-3-methyl-1H-pyrazol-4-yl)sulfonyl)-2-(((N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(((N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (4-((3-(2,2-difluoroethoxy)-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(((N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (4-((1-(2,2-difluoroethyl)-3-ethoxy-1H-pyrazol-4-yl)sulfonyl)-2-(((N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-2-(((N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (4-((2-methoxy-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)sulfonyl)-2-(((N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-tert-butyl    (2-((pyridin-2-ylthio)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-tert-butyl    (2-((cyclopentylthio)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-tert-butyl    (2-((benzylthio)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-tert-butyl    (2-((tert-butylthio)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-tert-butyl    (2-(((4,5-dimethyl-1H-imidazol-2-yl)thio)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-tert-butyl    (2-((phenylthio)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-tert-butyl    (2-((methylthio)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-tert-butyl    (2-((pyridin-2-ylsulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-tert-butyl    (2-((tert-butylsulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-tert-butyl    (2-(((4,5-dimethyl-1H-imidazol-2-yl)sulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-tert-butyl    (2-((phenylsulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-tert-butyl    (2-((cyclopentylsulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-tert-butyl    (2-((benzylsulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-tert-butyl    (2-((methylsulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-tert-butyl    (2-((pyridin-2-ylsulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-tert-butyl    (2-((N-cyclopropylsulfamoyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-tert-butyl    (2-((N-(2,2,2-trifluoroethyl)sulfamoyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-tert-butyl    (2-((morpholinosulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-tert-butyl    (2-((N-ethylsulfamoyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-tert-butyl    (2-((N,N-dimethylsulfamoyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   1,1,1-trifluoro-2-methylpropan-2-yl    (S)-(4-((3-ethoxy-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   [(2S,3S and    2R,3R)-4-(3-cyano-benzenesulfonyl)-2-hydroxymethyl-3-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamic    acid 2,2-dimethyl-propyl ester;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (4-((4-fluorophenyl)sulfonyl)-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-3-(hydroxymethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (4-((4-fluorophenyl)sulfonyl)-3-(hydroxymethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   [(S)-4-(3-cyano-benzenesulfonyl)-2-(2,4-dioxo-oxazolidin-3-ylmethyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamic    acid tert-butyl ester;-   (1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl    ((S)-4-((3-cyanophenyl)sulfonyl)-2-((2,4-dioxooxazolidin-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-neopentyl    (4-((3-cyanophenyl)sulfonyl)-2-((2,4-dioxooxazolidin-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (1S,4R)-bicyclo[2.2.1]heptan-2-yl((S)-2-((2,4-dioxooxazolidin-3-yl)methyl)-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-((2,4-dioxooxazolidin-3-yl)methyl)-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-neopentyl    (2-((2,4-dioxooxazolidin-3-yl)methyl)-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (tetrahydro-2H-pyran-2-yl)methyl    ((S)-2-((2,4-dioxooxazolidin-3-yl)methyl)-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (2S)-bicyclo[2.2.1]heptan-2-yl((S)-4-((3-cyanophenyl)sulfonyl)-2-((2,4-dioxooxazolidin-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (2S)-bicyclo[2.2.1]heptan-2-yl((S)-2-((2,4-dioxooxazolidin-3-yl)methyl)-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   [(S)-4-(3-cyano-benzenesulfonyl)-2-dimethylaminomethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamic    acid tert-butyl ester;-   [(S)-4-(3-cyano-benzenesulfonyl)-2-dimethylaminomethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamic    acid 2,2-dimethyl-propyl ester;-   (1S,4R)-bicyclo[2.2.1]heptan-2-yl((S)-4-((3-cyanophenyl)sulfonyl)-2-((dimethylamino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl((S)-4-((3-cyanophenyl)sulfonyl)-2-((dimethylamino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-neopentyl    (2-((dimethylamino)methyl)-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   bicyclo[2.2.1]heptan-2-yl    ((S)-2-((dimethylamino)methyl)-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (2S)-bicyclo[2.2.1]heptan-2-yl    ((S)-2-((dimethylamino)methyl)-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tetrahydro-2H-pyran-4-yl(4-((3-cyanophenyl)sulfonyl)-2-((dimethylamino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-methyl    2-(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate;-   (S)-methyl    2-(6-((tert-butoxycarbonyl)amino)-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate;-   (S)-methyl    2-(6-((tert-butoxycarbonyl)amino)-4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate;-   (S)-methyl    2-(6-((tert-butoxycarbonyl)amino)-4-((4-fluoro-3-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate;-   (R)-methyl    2-(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate;-   (S)-methyl    2-(4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate;-   [(S)-6-tert-butoxycarbonylamino-4-(1-difluoromethyl-3-methyl-1H-pyrazole-4-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl]-acetic    acid;-   (S)-2-(6-((tert-butoxycarbonyl)amino)-4-((4-fluoro-3-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetic    acid;-   (S)-2-(6-((tert-butoxycarbonyl)amino)-4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetic    acid;-   (S)-2-(6-((tert-butoxycarbonyl)amino)-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetic    acid;-   (S)-2-(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetic    acid;-   (S)-2-(6-((tert-butoxycarbonyl)amino)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetic    acid;-   (S)-2-(4-((4-fluorophenyl)sulfonyl)-6-(((neopentyloxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetic    acid;-   (S)-2-(6-((tert-butoxycarbonyl)amino)-4-((3-chlorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetic    acid;-   (S)-2-(4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetic    acid;-   (R)-6-((tert-butoxycarbonyl)amino)-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylic    acid;-   (R)-6-((tert-butoxycarbonyl)amino)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylic    acid;-   (R)-6-((tert-butoxycarbonyl)amino)-4-((4-fluoro-3-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylic    acid;-   (R)-4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylic    acid;-   (R)-6-((tert-butoxycarbonyl)amino)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylic    acid;-   (R)-6-((tert-butoxycarbonyl)amino)-4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylic    acid;-   [(S)-2-(2-azetidin-1-yl-2-oxo-ethyl)-4-(1-difluoromethyl-3-methyl-1H-pyrazole-4-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamic    acid tert-butyl ester;-   [(S)-2-(2-azetidin-1-yl-2-oxo-ethyl)-4-(1-difluoromethyl-3-methyl-1H-pyrazole-4-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamic    acid 1,2,2-trimethyl-propyl ester;-   (S)-tert-butyl    (2-(2-amino-2-oxoethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-amino-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (4-((4-fluorophenyl)sulfonyl)-2-(2-(methylamino)-2-oxoethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-(methylamino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-(dimethylamino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   tert-butyl    (2-(2-(dimethylamino)-2-oxoethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-tert-butyl    (4-((3-chloro-4-fluorophenyl)sulfonyl)-2-(2-(methylamino)-2-oxoethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (4-((3-chloro-4-fluorophenyl)sulfonyl)-2-(2-(methylamino)-2-oxoethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   1,1,1-trifluoro-2-methylpropan-2-yl    (4-((3-chloro-4-fluorophenyl)sulfonyl)-2-(2-(methylamino)-2-oxoethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-tert-butyl    (2-(2-(oxazolidin-3-yl)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-((cyclobutylmethyl)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-oxo-2-(3,3,3-trifluoropropyl)amino)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-(isobutylamino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-(((1H-pyrazol-4-yl)methyl)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-(((1-methyl-1H-pyrazol-4-yl)methyl)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-(((1H-pyrazol-3-yl)methyl)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-(((1-isopropyl-1H-pyrazol-4-yl)methyl)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-oxo-2-((pyrazolo[1,5-a]pyridin-3-ylmethyl)amino)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-(((1-ethyl-1H-pyrazol-3-yl)methyl)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-(1-methylpyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-(((1-methyl-1H-pyrazol-3-yl)methyl)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-(((1-ethyl-1H-pyrazol-4-yl)methyl)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-(((1-ethyl-5-methyl-1H-pyrazol-4-yl)methyl)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-(((1,5-dimethyl-1H-pyrazol-4-yl)methyl)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate-   (S)-tert-butyl    (2-(2-(((1-benzyl-1H-pyrazol-4-yl)methyl)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-3-(2-(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetamido)propanoic    acid-   (S)-methyl    3-(2-(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetamido)propanoate;-   (S)-tert-butyl    (2-(2-oxo-2-((4-(trifluoromethyl)benzyl)amino)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-(benzylamino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-((cyclopropylmethyl)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-oxo-2-(propylamino)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-(ethylamino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-(oxazolidin-3-yl)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-neopentyl    (2-(2-(methylamino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-(((2H-tetrazol-5-yl)methyl)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-((2-hydroxyethyl)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-(tert-butylamino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   tert-butyl    ((2S)-2-(2-(2-methylazetidin-1-yl)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-(3-cyanoazetidin-1-yl)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-(3-methoxyazetidin-1-yl)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-(azetidin-1-yl)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-(azetidin-1-yl)-2-oxoethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-(3-methylazetidin-1-yl)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-neopentyl    (2-(2-(azetidin-1-yl)-2-oxoethyl)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-tert-butyl    (2-carbamoyl-4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-carbamoyl-4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-tert-butyl    (2-carbamoyl-4-((4-fluoro-3-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-methyl    3-(6-((tert-butoxycarbonyl)amino)-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamido)propanoate;-   (R)-tert-butyl    (2-carbamoyl-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-tert-butyl    (4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-2-(dimethylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-3-(6-((tert-butoxycarbonyl)amino)-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamido)propanoic    acid;-   tert-butyl    (2-(2-cyanopropan-2-yl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R and S)    2-(4-((4-fluorophenyl)sulfonyl)-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-methylpropanoic    acid;-   (R and    S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-2-(2-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-oxo-2-(trifluoromethylsulfonamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-neopentyl    (2-(2-(cyclopropanesulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-neopentyl    (4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-oxo-2-(trifluoromethylsulfonamido)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-oxo-2-(thiazole-2-sulfonamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-oxo-2-(pyridine-4-sulfonamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-(1,1-dimethylethylsulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-oxo-2-(5-(trifluoromethyl)pyridine-2-sulfonamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-neopentyl    (4-((4-fluorophenyl)sulfonyl)-2-(2-oxo-2-(trifluoromethylsulfonamido)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-oxo-2-(pyridine-2-sulfonamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-oxo-2-(pyridine-3-sulfonamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-oxo-2-(4-(trifluoromethyl)pyridine-2-sulfonamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-oxo-2-(1H-pyrazole-4-sulfonamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-(4-methylpyridine-2-sulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-(2-fluoro-5-methylphenylsulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-(2-fluorophenylsulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-oxo-2-(2-(trifluoromethyl)phenylsulfonamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-oxo-2-(3-(trifluoromethyl)phenylsulfonamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-(3-fluorophenylsulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-(cyclopropanesulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-(4-methylphenylsulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-(1-methylethylsulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-(ethylsulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-(methylsulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-neopentyl    (2-(2-(cyclopropanesulfonamido)-2-oxoethyl)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-(cyclopentanesulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-(2-methylphenylsulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-(4-fluorophenylsulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-(2,5-dimethylphenylsulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-oxo-2-(4-propylphenylsulfonamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-(6-methylpyridine-2-sulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-neopentyl    (2-(2-(cyclopropanesulfonamido)-2-oxoethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-(2-(2-(methoxyamino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamic    acid;-   (S)-tert-butyl    (2-(2-oxo-2-((2-(trifluoromethyl)phenoxy)amino)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-oxo-2-((pyridin-3-ylmethoxy)amino)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-oxo-2-(((4-(trifluoromethyl)benzyl)oxy)amino)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-oxo-2-(((3-(trifluoromethyl)benzyl)oxy)amino)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-((4-fluorophenoxy)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-((cyclopentyloxy)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-(ethoxyamino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-((benzyloxy)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-(((4-methylbenzyl)oxy)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-(isopropoxyamino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-oxo-2-(propoxyamino)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-tert-butyl    (4-((4-fluorophenyl)sulfonyl)-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-1,1,1-trifluoro-2-methylpropan-2-yl    (4-((4-fluorophenyl)sulfonyl)-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-tert-butyl    (4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-1,1,1-trifluoro-2-methylpropan-2-yl    (4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-tert-butyl    (4-((3-chloro-4-fluorophenyl)sulfonyl)-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-tert-butyl    (4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (4-((4-fluorophenyl)sulfonyl)-2-((4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-2-((4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-((4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-tert-butyl    (4-((4-fluorophenyl)sulfonyl)-2-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   tert-butyl    (2-(cyanomethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   tert-butyl    (2-(2-hydroxypropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-amino-2-methylpropyl)-4-((3-(trifluoromethyl)phenyl)    sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-acetamido-2-methylpropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-propionamidoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   tert-butyl    ((2S)-2-(2-(2-hydroxypropanamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-(oxetane-3-carboxamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-isobutyramidoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-acetamidoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-(cyclopropanecarboxamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (4-((4-fluorophenyl)sulfonyl)-2-(2-propionamidoethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-acetamidoethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   tert-butyl    ((2S)-4-((4-fluorophenyl)sulfonyl)-2-(2-(2-hydroxypropanamido)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-(cyclopropanecarboxamido)ethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-neopentyl    (4-((4-fluorophenyl)sulfonyl)-2-(2-propionamidoethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-neopentyl    (2-(2-acetamidoethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-neopentyl    (2-(2-(cyclopropanecarboxamido)ethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (2-(2-amino-2-methylpropyl)-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (2-(2-amino-2-methylpropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-(2-oxopyrrolidin-1-yl)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (2-(2-(2-oxopyrrolidin-1-yl)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-acetamido-2-methylpropyl)-4-((3-chloro-4-fluorophenyl)    sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-acetamido-2-methylpropyl)-4-((3,4-difluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-acetamido-2-methylpropyl)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-acetamido-2-methylpropyl)-4-((1-(difluoromethyl)-5-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-acetamido-2-methylpropyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-tert-butyl    (2-(2-acetamido-2-methylpropyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (2-(2-acetamido-2-methylpropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (2-(2-acetamido-2-methylpropyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (2-(2-acetamido-2-methylpropyl)-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (2-(2-acetamido-2-methylpropyl)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (4-((4-fluorophenyl)sulfonyl)-2-(2-methyl-2-(methylsulfonamido)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (2-(2-acetamido-2-methylpropyl)-4-((3,4-difluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-4-fluorophenyl)sulfonyl)-2-(2-methyl-2-(methylsulfonamido)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (4-((3,4-difluorophenyl)sulfonyl)-2-(2-methyl-2-(methylsulfonamido)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (2-(2-(cyclopropanesulfonamido)-2-methylpropyl)-4-((3,4-difluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (2-(2-methyl-2-(methylsulfonamido)propyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (2-(2-(cyclopropanesulfonamido)-2-methylpropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (4-((3-chloro-4-fluorophenyl)sulfonyl)-2-(2-methyl-2-(methylsulfonamido)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (2-(2-(cyclopropanesulfonamido)-2-methylpropyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-(cyclopropanesulfonamido)-2-methylpropyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (2-(2-methyl-2-(trifluoromethylsulfonamido)propyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (2-(2-(2-(dimethylamino)-2-oxoacetamido)-2-methylpropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (2-(2-acetamido-2-methylpropyl)-4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-acetamido-2-methylpropyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (2-(2-acetamido-2-methylpropyl)-4-((3-methoxy-1,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (2-(2-acetamido-2-methylpropyl)-4-((1-(difluoromethyl)-3-ethoxy-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (2-(2-acetamido-2-methylpropyl)-4-((3-(difluoromethoxy)-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   tert-butyl    (2-(2-hydroxyethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   tert-butyl    (2-((1H-imidazol-2-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   tert-butyl    (2-((1-methyl-1H-imidazol-2-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (4-((4-fluorophenyl)sulfonyl)-2-((2-oxopyrrolidin-1-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-((1H-pyrazol-1-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-((2H-1,2,3-triazol-2-yl)methyl)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-((4H-1,2,4-triazol-4-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-((1H-1,2,4-triazol-1-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-((1H-1,2,3-triazol-1-yl)methyl)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-((1H-1,2,3-triazol-1-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-((2H-1,2,3-triazol-2-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-tert-butyl    (2-((pyridin-2-yloxy)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-((2-oxopyridin-1(2H)-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-((5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   tert-butyl    (2-(2-hydroxy-2-methylpropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-((3-hydroxyazetidin-1-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(((3-methyloxetan-3-yl)amino)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   tert-butyl    ((2S)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-2-(((1,1,1-trifluoropropan-2-yl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   1,1,1-trifluoro-2-methylpropan-2-yl((2S)-4-((4-fluorophenyl)sulfonyl)-2-(2-methylazetidin-1-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (4-((4-fluorophenyl)sulfonyl)-2-(3-hydroxyazetidin-1-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(azetidin-1-ylmethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)carbamate;-   [(R)-1-((3-chloro-benzenesulfonyl)-3-hydroxymethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl]-carbamic    acid tert-butyl ester;-   [(S)-1-(3-chloro-benzenesulfonyl)-3-(2,4-dioxo-oxazolidin-3-ylmethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl]-carbamic    acid tert-butyl ester;-   4-[(S)-6-amino-4-((3-chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-2-ylmethyl]-1-methyl-piperazin-2-one;-   (S)-tert-butyl    (5-((4-fluorophenyl)sulfonyl)-6-methyl-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate;-   (S)-benzyl tert-butyl    (1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydro-1,5-naphthyridine-3,7-diyl)dicarbamate;-   benzyl tert-butyl    (1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydro-1,5-naphthyridine-3,7-diyl)dicarbamate;-   benzyl tert-butyl    (1-((3-cyanophenyl)sulfonyl)-1,2,3,4-tetrahydro-1,5-naphthyridine-3,7-diyl)dicarbamate;-   benzyl tert-butyl    (1-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-1,2,3,4-tetrahydro-1,5-naphthyridine-3,7-diyl)dicarbamate;-   (S)-benzyl    (5-((4-fluorophenyl)sulfonyl)-7-(2-oxopyrrolidin-1-yl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate;-   (S)-neopentyl    (5-((4-fluorophenyl)sulfonyl)-7-(2-oxopyrrolidin-1-yl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate;-   (R)-neopentyl    (5-((4-fluorophenyl)sulfonyl)-7-(2-oxopyrrolidin-1-yl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate;-   tert-butyl    (5-((4-fluorophenyl)sulfonyl)-7-hydroxy-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate;-   (R)-neopentyl    (5-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-7-(hydroxymethyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate;-   (S)-neopentyl    (5-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-7-(hydroxymethyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate;-   tert-butyl    (7-(hydroxymethyl)-5-(m-tolylsulfonyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate;-   tert-butyl    (5-((3,4-difluorophenyl)sulfonyl)-7-(hydroxymethyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate;-   (R or S)-neopentyl    (5-((4-fluorophenyl)sulfonyl)-7-(hydroxymethyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate;-   (S or R)-neopentyl    (5-((4-fluorophenyl)sulfonyl)-7-(hydroxymethyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate;-   neopentyl    ((S)-5-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate;-   1,1,1-trifluoro-2-methylpropan-2-yl    (4-((4-fluorophenyl)sulfonyl)-2-(2,2,2-trifluoroacetyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   2,2,2-trifluoro-1,1-dimethylethyl    [(2S)-4-{[1-(difluoromethyl)-3-(2-hydroxyethoxy)-1H-pyrazol-4-yl]sulfonyl}-2-{[(methylsulfamoyl)amino]methyl}-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbamate;-   2,2,2-trifluoro-1,1-dimethylethyl    [(2S)-2-[2-(acetylamino)-2-methylpropyl]-4-{[1-ethyl-3-(2-hydroxyethoxy)-1H-pyrazol-4-yl]sulfonyl}-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbamate;-   1,1,1-trifluoro-2-methylpropan-2-yl    ((R)-4-((3,4-difluorophenyl)sulfonyl)-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   1,1,1-trifluoro-2-methylpropan-2-yl    ((S)-4-((3,4-difluorophenyl)sulfonyl)-2-((R)-2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   1,1,1-trifluoro-2-methylpropan-2-yl    ((R)-4-((3,4-difluorophenyl)sulfonyl)-2-((R)-2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   1,1,1-trifluoro-2-methylpropan-2-yl    ((S)-4-((3,4-difluorophenyl)sulfonyl)-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   1,1,1-trifluoro-2-methylpropan-2-yl    ((R)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   1,1,1-trifluoro-2-methylpropan-2-yl    ((R)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-((R)-2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   1,1,1-trifluoro-2-methylpropan-2-yl    ((S)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   1,1,1-trifluoro-2-methylpropan-2-yl    ((R)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-((R)-2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   1,1,1-trifluoro-2-methylpropan-2-yl    (4-((4-fluorophenyl)sulfonyl)-2-(2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   1,1,1-trifluoro-2-methylpropan-2-yl    ((S)-2-((R)-1-amino-2,2,2-trifluoroethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   1,1,1-trifluoro-2-methylpropan-2-yl    ((S)-2-((S)-1-amino-2,2,2-trifluoroethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   1,1,1-trifluoro-2-methylpropan-2-yl    ((R)-2-((R)-1-amino-2,2,2-trifluoroethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   1,1,1-trifluoro-2-methylpropan-2-yl    ((R)-2-((S)-1-amino-2,2,2-trifluoroethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (2-(2-(ethylsulfonyl)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (2-(2-(ethylsulfonyl)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   1,1,1-trifluoro-2-methylpropan-2-yl    ((2S,3R)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3-methyl-2-(((N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   1,1,1-trifluoro-2-methylpropan-2-yl    N-[(2S,3R)-2-[(1S)-1-[[(benzyloxy)carbonyl]amino]ethyl]-4-[(3,4-difluorobenzene)sulfonyl]-3-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbamate;-   1,1,1-trifluoro-2-methylpropan-2-yl    (3-(acetamidomethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-((1-carbamoylcyclopropyl)methyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-((1-carbamoylcyclopropyl)methyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   1,1,1-trifluoro-2-methylpropan-2-yl    ((S)-2-((R)-3-amino-2-cyclopropyl-3-oxopropyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   1,1,1-trifluoro-2-methylpropan-2-yl    ((S)-2-((S)-3-amino-2-cyclopropyl-3-oxopropyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(3-amino-2,2-dimethyl-3-oxopropyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(3-amino-2,2-dimethyl-3-oxopropyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-1,1,1-trifluoro-2-methylpropan-2-yl    (2-(3-amino-2,2-dimethyl-3-oxopropyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (2-(3-amino-2,2-dimethyl-3-oxopropyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   2,2,2-trifluoro-1,1-dimethylethyl    {(2S)-2-(3-amino-2,2-dimethyl-3-oxopropyl)-4-[(4-fluoro-3-methoxyphenyl)sulfonyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbamate;-   1,1,1-trifluoro-2-methylpropan-2-yl((S)-2-((S)-3-amino-2-cyclopropyl-3-oxopropyl)-4-((4-fluoro-3-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   1,1,1-trifluoro-2-methylpropan-2-yl((S)-2-((S)-3-amino-2-cyclopropyl-3-oxopropyl)-4-((3-ethoxy-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   1,1,1-trifluoro-2-methylpropan-2-yl((S)-2-((R)-3-amino-2-cyclopropyl-3-oxopropyl)-4-((4-fluoro-3-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   1,1,1-trifluoro-2-methylpropan-2-yl    ((S)-2-((R)-3-amino-2-cyclopropyl-3-oxopropyl)-4-((3-ethoxy-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   2,2,2-trifluoro-1,1-dimethylethyl    [(2S)-2-(3-amino-2,2-dimethyl-3-oxopropyl)-4-{[5-(trifluoromethyl)pyridin-3-yl]sulfonyl}-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbamate;-   2,2,2-trifluoro-1,1-dimethylethyl    {2-(3-amino-2,2-dimethyl-3-oxopropyl)-4-[(3-ethoxy-1-ethyl-1H-pyrazol-4-yl)sulfonyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbamate;-   2,2,2-trifluoro-1,1-dimethylethyl    [2-(3-amino-2,2-dimethyl-3-oxopropyl)-4-{[1-ethyl-3-(2-hydroxyethoxy)-1H-pyrazol-4-yl]sulfonyl}-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbamate;-   (S)-methyl    2-((4-((2-(3-amino-2,2-dimethyl-3-oxopropyl)-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-2H-benzo[b][1,4]oxazin-4(3H)-yl)sulfonyl)-1-ethyl-1H-pyrazol-3-yl)oxy)acetate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-cyanoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-((1-cyanocyclopropyl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-1,1,1-trifluoro-2-methylpropan-2-yl    (4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-((1-cyanocyclopropyl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-cyano-2-methylpropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-1,1,1-trifluoro-2-methylpropan-2-yl    (4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-cyano-2-methylpropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-cyano-2-methylpropyl)-4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-cyano-2-methylpropyl)-4-((4-fluoro-3-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-1,1,1-trifluoro-2-methylpropan-2-yl    (2-(2-cyano-2-methylpropyl)-4-((4-fluoro-3-methylphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (2-(2-cyano-2-methylpropyl)-4-((4-fluoro-3-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-cyano-2-methylpropyl)-4-((4-fluoro-3-methylphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-cyano-2-methylpropyl)-4-((3-ethoxy-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (2-(2-cyano-2-methylpropyl)-4-((3-ethoxy-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (2-(3-(cyclopropanesulfonamido)-3-oxopropyl)-4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   1,1,1-trifluoro-2-methylpropan-2-yl    ((S)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-((S)-3-(cyclopropanesulfonamido)-2-methyl-3-oxopropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   1,1,1-trifluoro-2-methylpropan-2-yl    ((S)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-((R)-3-(cyclopropanesulfonamido)-2-methyl-3-oxopropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   2,2,2-trifluoro-1,1-dimethylethyl    [(2S)-2-{3-[(tert-butylsulfonyl)amino]-3-oxopropyl}-4-{[4-fluoro-3-(trifluoromethyl)phenyl]sulfonyl}-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbamate;-   2,2,2-trifluoro-1,1-dimethylethyl    [(2S)-4-{[4-fluoro-3-(trifluoromethyl)phenyl]sulfonyl}-2-(3-{[(4-methylphenyl)sulfonyl]amino}-3-oxopropyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbamate;-   2,2,2-trifluoro-1,1-dimethylethyl    [(2S)-4-{[4-fluoro-3-(trifluoromethyl)phenyl]sulfonyl}-2-(3-oxo-3-{[(trifluoromethyl)sulfonyl]amino}propyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbamate;-   1,1,1-trifluoro-2-methylpropan-2-yl ((S)-2-((R and    S)-3-(cyclopropanesulfonamido)-2-methyl-3-oxopropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   1,1,1-trifluoro-2-methylpropan-2-yl    ((S)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-((R)-3-(1,1-dimethylethylsulfonamido)-2-methyl-3-oxopropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   1,1,1-trifluoro-2-methylpropan-2-yl((S)-2-((R)-3-(cyclopropanesulfonamido)-2-methyl-3-oxopropyl)-4-((4-fluoro-3-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   1,1,1-trifluoro-2-methylpropan-2-yl((S)-2-((R)-3-(1,1-dimethylethylsulfonamido)-2-methyl-3-oxopropyl)-4-((4-fluoro-3-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   1,1,1-trifluoro-2-methylpropan-2-yl((S)-2-((S)-3-(cyclopropanesulfonamido)-2-methyl-3-oxopropyl)-4-((4-fluoro-3-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   1,1,1-trifluoro-2-methylpropan-2-yl    ((S)-2-((S)-3-(1,1-dimethylethylsulfonamido)-2-methyl-3-oxopropyl)-4-((4-fluoro-3-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   1,1,1-trifluoro-2-methylpropan-2-yl    ((S)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-((S)-3-(1,1-dimethylethylsulfonamido)-2-methyl-3-oxopropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-2-(oxetan-3-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (2-(2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-methyl-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-methyl-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   2,2,2-trifluoro-1,1-dimethylethyl    [(2S)-2-[2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethyl]-4-{[3-(trifluoromethyl)phenyl]sulfonyl}-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbamate;-   2,2,2-trifluoro-1,1-dimethylethyl    {(2S)-4-[(3-cyclopropylphenyl)sulfonyl]-2-[2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbamate;-   tert-butyl    {(2S)-4-[(3-cyclopropylphenyl)sulfonyl]-2-[2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-tert-butyl    (4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-1,1,1-trifluoro-2-methylpropan-2-yl    (4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-methyl-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-1,1,1-trifluoro-2-methylpropan-2-yl    (4-((4-fluoro-3-methoxyphenyl)sulfonyl)-2-(2-methyl-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-methyl-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluoro-3-methoxyphenyl)sulfonyl)-2-(2-methyl-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-methyl-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   2,2,2-trifluoro-1,1-dimethylethyl    {(2S)-4-[(3-cyclopropylphenyl)sulfonyl]-2-[2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbamate;-   2,2,2-trifluoro-1,1-dimethylethyl    {(2S)-4-[(4-fluoro-3-methoxyphenyl)sulfonyl]-2-[2-methyl-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-(1H-tetrazol-5-yl)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   2,2,2-trifluoro-1,1-dimethylethyl    {(2S)-4-[(3-cyclopropylphenyl)sulfonyl]-2-[2-(1H-tetrazol-5-yl)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbamate;-   2,2,2-trifluoro-1,1-dimethylethyl    [(2S)-2-[2-(1H-tetrazol-5-yl)ethyl]-4-{[2-(trifluoromethyl)pyridin-4-yl]sulfonyl}-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-(1H-tetrazol-5-yl)ethyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-1,1,1-trifluoro-2-methylpropan-2-yl(24    hydroxymethyl)-5-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;-   (R)-1,1,1-trifluoro-2-methylpropan-2-yl(5-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((ethylsulfonyl)methyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl(5-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((ethylsulfonyl)methyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate;-   (S)-3-(1-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)propanoic    acid;-   (R)-3-(1-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)propanoic    acid;-   1,1,1-trifluoro-2-methylpropan-2-yl    (1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamate;-   2,2,2-trifluoro-1,1-dimethylethyl    {1-[(3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl]-1,2,3,4-tetrahydroquinolin-7-yl}carbamate;-   2,2,2-trifluoro-1,1-dimethylethyl    (1-{[1-ethyl-3-(2-hydroxyethoxy)-1H-pyrazol-4-yl]sulfonyl}-1,2,3,4-tetrahydroquinolin-7-yl)carbamate;-   2,2,2-trifluoro-1,1-dimethylethyl    {1-[(3-ethoxy-1-ethyl-1H-pyrazol-4-yl)sulfonyl]-1,2,3,4-tetrahydroquinolin-7-yl}carbamate;-   2,2,2-trifluoro-1,1-dimethylethyl    (1-{[2-(trifluoromethyl)pyridin-4-yl]sulfonyl}-1,2,3,4-tetrahydroquinolin-7-yl)carbamate;-   (R)-1,1,1-trifluoro-2-methylpropan-2-yl    (3-(acetamidomethyl)-1-((4-fluoro-3-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamate;-   (S)-1,1,1-trifluoro-2-methylpropan-2-yl    (3-(acetamidomethyl)-1-((4-fluoro-3-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamate;-   (R)-3-(1-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydroquinolin-3-yl)propanoic    acid;-   (S)-3-(1-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydroquinolin-3-yl)propanoic    acid;-   (R)-3-(7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1-((5-(trifluoromethyl)pyridin-3-yl)sulfonyl)-1,2,3,4-tetrahydroquinolin-3-yl)propanoic    acid;-   (R)-3-(1-((4-fluoro-3-methoxyphenyl)sulfonyl)-7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydroquinolin-3-yl)propanoic    acid;-   (S)-3-(7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1-((5-(trifluoromethyl)pyridin-3-yl)sulfonyl)-1,2,3,4-tetrahydroquinolin-3-yl)propanoic    acid;-   (S)-3-(1-((4-fluoro-3-methoxyphenyl)sulfonyl)-7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydroquinolin-3-yl)propanoic    acid;-   1,1,1-trifluoro-2-methylpropan-2-yl    (5-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-8-oxo-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate;    and-   1,1,1-trifluoro-2-methylpropan-2-yl    (1-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-4-oxo-1,2,3,4-tetrahydroquinolin-7-yl)carbamate.

The invention also provides a compound of Formula (I) or apharmaceutically acceptable salt thereof in purified form.

Uses of the Compounds

Compounds of Formula (I) alter the interaction of coregulator proteinswith Retinoic Acid Receptor-related Orphan Receptor gamma t (RORgammaT)and thereby antagonize RORgammaT-mediated transcriptional activity, andas such are useful in the treatment of diseases and conditions in whichinhibition of RORgammaT is desirable, such as autoimmune andinflammatory diseases and disorders.

Accordingly, another embodiment of the present invention provides amethod for treating a disease or condition mediated by RORgammaT in asubject comprising administering to the subject an amount of a compoundof Formula (I) that is effective for treating the disease or conditionmediated by RORgammaT in the subject.

The compounds according to the invention can be used in therapy.

A further aspect of the invention resides in the use of compounds ofFormula (I) for the treatment of RORgammaT-mediated diseases orRORgammaT-mediated conditions.

Another aspect of the invention resides in the use of a compound ofFormula (I) in the manufacture of a medicament for the treatment of adisease or condition mediated by RORgammaT.

Another aspect of the invention resides in the use of compounds ofFormula (I) for the treatment of autoimmune diseases, in particularthose diseases in which Th17 cells and non-Th17 cells, which expressTh17 hallmark cytokines, play a prominent role. These include, but arenot limited to, the treatment of rheumatoid arthritis, psoriasis,inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis),ankylosing spondylitis, and multiple sclerosis.

In another aspect, compounds of Formula (I) can be used for treatment ofinflammatory diseases in which Th17 cells and/or non-Th17 cells, whichexpress Th17 hallmark cytokines, play a prominent role, such as but notlimited to respiratory diseases, osteoarthritis, and asthma. Also,compounds of Formula (I) can be used for treatment of infectiousdiseases in which Th17 cells and/or non-Th17 cells, which express Th17hallmark cytokines, play a prominent role, such as but not limited tomucosal leishmaniasis.

In another aspect, compounds of Formula (I) can be used in the treatmentof cancer. Those skilled in the art will recognize the term “cancer” tobe a name for diseases in which the body's cells become abnormal anddivide without control. The term cancer includes, but is not limited to,colorectal, lung, and pancreatic cancer.

Compounds of Formula (I) can also be used for treatment of otherdiseases in which Th17 cells and/or non-Th17 cells, which express Th17hallmark cytokines, play a prominent role, such as but not limited toKawasaki disease and Hashimoto's thyroiditis.

In one aspect, the disease or condition is an autoimmune disease orinflammatory disease. The disease or condition includes, but is notlimited to, multiple sclerosis, inflammatory bowel disease (e.g.,Crohn's disease, ulcerative colitis), psoriasis, rheumatoid arthritis,asthma, osteoarthritis, Kawasaki disease, Hashimoto's thyroiditis, andmucosal leishmaniasis.

In another aspect, the compounds of Formula (I) can be used in therapiesto treat or prevent multiple sclerosis, inflammatory bowel disease(e.g., Crohn's disease, ulcerative colitis), psoriasis, rheumatoidarthritis, asthma, osteoarthritis, Kawasaki disease, Hashimoto'sthyroiditis, and mucosal leishmaniasis.

In another aspect, the compounds of Formula (I) can be used to treat orprevent psoriasis.

In yet another aspect, the compounds of Formula (I) can be used to treatinflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis).

In another aspect, the compound of Formula (I) can be used to treatcolorectal cancer.

In another aspect, the compound of Formula (I) can be used to treat lungcancer.

In another aspect, the compound of Formula (I) can be used to treatpancreatic cancer.

Route of Administration/Dosage

The compounds of this invention can be administered for the treatment orprevention of afflictions, diseases, and illnesses according to theinvention by any means that effects contact of the active ingredientcompound with the site of action in the body of a warm-blooded animal.For example, administration can be oral, topical, including transdermal,ocular, buccal, intranasal, inhalation, intravaginal, rectal,intracisternal, and parenteral. The term “parenteral” as used hereinrefers to modes of administration that include subcutaneous,intravenous, intramuscular, intraarticular injection or infusion,intrasternal and intraperitoneal. For the purpose of this disclosure, awarm-blooded animal is a member of the animal kingdom possessed of ahomeostatic mechanism and includes mammals and birds.

The compounds can be administered by any conventional means availablefor use in conjunction with pharmaceuticals, either as individualtherapeutic agents or in a combination of therapeutic agents. They canbe administered alone, but are generally administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The dosage administered will be dependent on the age, health, and weightof the recipient; the extent of disease; kind of concurrent treatment,if any; frequency of treatment; and the nature of the effect desired.Usually, a daily dosage of active ingredient compound will be from about1.0-2000 milligrams per day. Ordinarily, from 10 to 500 milligrams perday in one or more applications is effective to obtain desired results.These dosages are the effective amounts for the treatment and preventionof afflictions, diseases, and illnesses described above, e.g.,autoimmune and inflammatory diseases and disorders.

Compositions include those suitable for oral, sublingual, subcutaneous,intravenous, intramuscular, nasal, local, or rectal administration, andthe like, all in unit dosage forms for administration.

For oral administration, the active ingredient may be presented asdiscrete units, such as tablets, capsules, powders, granulates,solutions, suspensions, and the like.

For parenteral administration, the pharmaceutical composition of theinvention may be presented in unit-dose or multi-dose containers, e.g.,injection liquids in predetermined amounts, for example in sealed vialsand ampoules, and may also be stored in a freeze dried (lyophilized)condition requiring only the addition of sterile liquid carrier, e.g.,water, prior to use.

Mixed with such pharmaceutically acceptable auxiliaries, e.g., asdescribed in the standard reference, Gennaro, A. R. et al., Remington:The Science and Practice of Pharmacy (20th Edition, Lippincott Williams& Wilkins, 2000, see especially Part 5: Pharmaceutical Manufacturing),the active agent may be compressed into solid dosage units, such aspills, tablets, or be processed into capsules or suppositories. By meansof pharmaceutically acceptable liquids the active agent can be appliedas a fluid composition, e.g., as an injection preparation, in the formof a solution, suspension, emulsion, or as a spray, e.g., a nasal spray.

For making solid dosage units, the use of conventional additives such asfillers, colorants, polymeric binders, and the like is contemplated. Ingeneral any pharmaceutically acceptable additive that does not interferewith the function of the active compounds can be used. Suitable carrierswith which the active agent of the invention can be administered assolid compositions include lactose, starch, cellulose derivatives, andthe like, or mixtures thereof, used in suitable amounts. For parenteraladministration, aqueous suspensions, isotonic saline solutions, andsterile injectable solutions may be used, containing pharmaceuticallyacceptable dispersing agents and/or wetting agents, such as propyleneglycol or butylene glycol.

Pharmaceutical Compositions

Another aspect of the present invention provides pharmaceuticalcompositions comprising a compound of Formula (I) or a pharmaceuticallyacceptable salt thereof and one or more pharmaceutically acceptableexcipients. The term “excipient” and “carrier” may be usedinterchangeably. The term “composition,” as in pharmaceuticalcomposition, is intended to encompass a product comprising the activeingredient(s), and the inert ingredient(s) (pharmaceutically acceptableexcipients) that make up the carrier, as well as any product thatresults, directly or indirectly, from combination, complexation, oraggregation of any two or more of the ingredients, or from dissociationof one or more of the ingredients, or from other types of reactions orinteractions of one or more of the ingredients. Accordingly, thepharmaceutical compositions of the present invention encompass anycomposition made by admixing a compound of Formula (I), additionalactive ingredient(s), and pharmaceutically acceptable excipients.

The pharmaceutical compositions of the present invention comprise acompound represented by Formula (I) (or pharmaceutically acceptablesalts thereof) as an active ingredient, a pharmaceutically acceptablecarrier, and optionally other therapeutic ingredients or adjuvants. Thecompositions include compositions suitable for oral, rectal, topical,and parenteral (including subcutaneous, intramuscular, and intravenous)administration, although the most suitable route in any given case willdepend on the particular host, and nature and severity of the conditionsfor which the active ingredient is being administered. Thepharmaceutical compositions may be conveniently presented in unit dosageform and prepared by any of the methods well known in the art ofpharmacy in light of the present disclosure.

The active ingredient can be administered orally in solid dosage forms,such as capsules, tablets, troches, dragées, granules, and powders, orin liquid dosage forms, such as elixirs, syrups, emulsions, dispersions,and suspensions. The active ingredient can also be administeredparenterally, in sterile liquid dosage forms, such as dispersions,suspensions, or solutions. Other dosages forms that can also be used toadminister the active ingredient as an ointment, cream, drops,transdermal patch, or powder for topical administration, as anophthalmic solution or suspension formation, i.e., eye drops, for ocularadministration, as an aerosol spray or powder composition for inhalationor intranasal administration, or as a cream, ointment, spray, orsuppository for rectal or vaginal administration.

Gelatin capsules can contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours, for example. Compressed tablets canbe sugar coated or film coated to mask any unpleasant taste and protectthe tablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid and its saltsand sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propylparaben,and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, A. Osol, a standard reference text in thisfield.

For administration by inhalation, the compounds of Formula (I) may beconveniently delivered in the form of an aerosol spray presentation frompressurized packs or nebulizers. The compounds may also be delivered aspowders which may be formulated and the powder composition may beinhaled with the aid of an insufflation powder inhaler device. Thepreferred delivery system for inhalation is a metered dose inhalation(MDI) aerosol, which may be formulated as a suspension or solution of acompound of Formula (I) in suitable propellants, such as fluorocarbonsor hydrocarbons.

For ocular administration, an ophthalmic preparation may be formulatedwith an appropriate weight percent solution or suspension of thecompounds of Formula (I) in an appropriate ophthalmic vehicle, such thatthe compound is maintained in contact with the ocular surface for asufficient time period to allow the compound to penetrate the cornealand internal regions of the eye.

Useful pharmaceutical dosage forms for administration of the compoundsof this invention include, but are not limited to, hard and soft gelatincapsules, tablets, parenteral injectables, and oral suspensions.

A large number of unit capsules are prepared by filling standardtwo-piece hard gelatin capsules each with 100 milligrams of powderedactive ingredient, 150 milligrams of lactose, 50 milligrams ofcellulose, and 6 milligrams magnesium stearate.

A mixture of active ingredient in a digestible oil such as soybean oil,cottonseed oil, or olive oil is prepared and injected by means of apositive displacement pump into gelatin to form soft gelatin capsulescontaining 100 milligrams of the active ingredient. The capsules arewashed and dried.

A large number of tablets are prepared by conventional procedures sothat the dosage unit is 100 milligrams of active ingredient, 0.2milligrams of colloidal silicon dioxide, 5 milligrams of magnesiumstearate, 275 milligrams of microcrystalline cellulose, 11 milligrams ofstarch and 98.8 milligrams of lactose. Appropriate coatings may beapplied to increase palatability or delay absorption.

A parenteral composition suitable for administration by injection isprepared by stirring 1.5% by weight of active ingredient in 10% byvolume propylene glycol. The solution is made to volume with water forinjection and sterilized.

An aqueous suspension is prepared for oral administration so that each 5milliliters contains 100 milligrams of finely divided active ingredient,100 milligrams of sodium carboxymethyl cellulose, 5 milligrams of sodiumbenzoate, 1.0 grams of sorbitol solution, U.S.P., and 0.025 millilitersof vanillin.

The same dosage forms can generally be used when the compounds of thisinvention are administered stepwise or in conjunction with anothertherapeutic agent. When drugs are administered in physical combination,the dosage form and administration route should be selected depending onthe compatibility of the combined drugs. Thus the term“coadministration” is understood to include the administration of thetwo agents concomitantly or sequentially, or alternatively as a fixeddose combination of the two active components.

The present invention also relates to a pharmaceutical compositioncomprising compounds of Formula (I) or pharmaceutically acceptable saltsthereof in admixture with pharmaceutically acceptable auxiliaries andoptionally other therapeutic agents. The auxiliaries must be“acceptable” in the sense of being compatible with the other ingredientsof the composition and not deleterious to the recipients thereof.

The invention further includes a pharmaceutical composition, ashereinbefore described, in combination with packaging material suitablefor said composition, said packaging material including instructions forthe use of the composition for the use as hereinbefore described.

The exact dose and regimen of administration of the active ingredient,or a pharmaceutical composition thereof, may vary with the particularcompound, the route of administration, and the age and condition of theindividual subject to whom the medicament is to be administered.

In general, parenteral administration requires lower dosages than othermethods of administration which are more dependent upon absorption.However, a dosage for humans preferably contains 0.0001-100 mg per kgbody weight. The desired dose may be presented as one dose or asmultiple subdoses administered at appropriate intervals throughout theday. The dosage as well as the regimen of administration may differbetween a female and a male recipient.

Combination Therapy

Compounds of Formula (I), and pharmaceutically acceptable salts andphysiologically functional derivatives (e.g., prodrugs) thereof, may beemployed alone or in combination with other therapeutic agents for thetreatment of diseases and conditions associated with inappropriate IL-17pathway activity. Combination therapies according to the presentinvention thus comprise the administration of at least one compound ofFormula (I) or a pharmaceutically acceptable salt thereof, or aphysiologically functional derivative thereof, and the use of at leastone other pharmaceutically active agent. The compound(s) of Formula (I)and the other pharmaceutically active agent(s) may be administeredtogether or separately and, when administered separately, this may occursimultaneously or sequentially in any order. The amounts of thecompound(s) of Formula (I) and the other pharmaceutically activeagent(s) and the relative timings of administration will be selected inorder to achieve the desired combined therapeutic effect.

For the treatment of the inflammatory and autoimmune diseases,rheumatoid arthritis, psoriasis, inflammatory bowel disease, ankylosingspondylitis, SLE (systemic lupus erythematosus), uveitis, atopicdermatitis, COPD, asthma, and allergic rhinitis, a compound of Formula(I) may be combined with one or more other active agents such as: (1)TNF-a inhibitors; (2) non-selective COX-1/COX-2 inhibitors; (3) COX-2inhibitors; (4) other agents for treatment of inflammatory andautoimmune diseases including glucocorticoids, methotrexate,leflunomide, sulfasalazine, azathioprine, cyclosporin, tacrolimus,penicillamine, bucillamine, actarit, mizoribine, lobenzarit,ciclesonide, hydroxychloroquine, d-penicillamine, aurothiomalate,auranofin or parenteral or oral gold, cyclophosphamide, Lymphostat-B,BAFF/APRIL inhibitors and CTLA-4-Ig or mimetics thereof; (5) leukotrienebiosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor or5-lipoxygenase activating protein (FLAP) antagonist; (6) LTD4 receptorantagonist; (7) PDE4 inhibitor; (8) antihistamine HI receptorantagonists; (9) a1- and a2-adrenoceptor agonist; (10) anticholinergicagents; (11) β-adrenoceptor agonists; (12) insulin-like growth factortype I (IGF-1) mimetic; (13) glucocorticosteroids; (14) kinaseinhibitors such as inhibitors of the Janus Kinases (JAK1 and/or JAK2and/or JAK3 and/or TYK2), p38 MAPK and IKK2; (15) B-cell targetingbiologics such as rituximab; (16) selective costimulation modulatorssuch as abatacept; (17) interleukin inhibitors, such as IL-1 inhibitoranakinra, IL-6 inhibitor tocilizumab, and IL12/IL-23 inhibitorustekinumab. The compound of Formula (I) may also be combined withanti-IL17 antibodies to obtain additive/synergistic responses for thetreatment of inflammatory and autoimmune diseases.

For the treatment of cancer, the compounds of Formula (I) can becombined with other therapeutic, chemotherapeutic, and anti-canceragents. Combinations of the compounds of Formula (I) with othertherapeutic, chemotherapeutic, and anti-cancer agents are within thescope of the invention. Examples of such agents can be found in CancerPrinciples and Practice of Oncology by V. T. Devita and S. Hellman(editors), 6^(th) edition (Feb. 15, 2001), Lippincott Williams & WilkinsPublishers. In light of the present disclosure, a person of ordinaryskill in the art would be able to discern which combinations of thecompounds of Formula (I) with the other therapeutic, chemotherapeutic,and anti-cancer agents would be useful based on the particularcharacteristics of the drugs and the cancer involved. The compounds ofFormula (I) may also be useful when co-administered with radiationtherapy. The compounds of Formula (I) can be present in the same dosageunit as the other therapeutic, chemotherapeutic, and anti-cancer agents.The compounds of Formula (I) and the other therapeutic,chemotherapeutic, and anti-cancer agents can also be present in separatedosage units.

It will be clear to a person skilled in the art that, where appropriate,the other therapeutic ingredient(s) may be used in the form of salts,for example as alkali metal or amine salts or as acid addition salts, orprodrugs, or as esters, for example lower alkyl esters, or as solvates,for example hydrates, to optimize the activity and/or stability and/orphysical characteristics, such as solubility, of the therapeuticingredient. It will be clear also that, where appropriate, the othertherapeutic ingredients may be used in optically pure form.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical composition and thus, pharmaceuticalcompositions comprising a combination as defined above together with apharmaceutically acceptable diluent or carrier represent a furtheraspect of the invention. These combinations are of particular interestin respiratory diseases and are conveniently adapted for inhaled orintranasal delivery.

The individual compounds of such combinations may be administered eithersequentially or simultaneously in separate or combined pharmaceuticalcompositions. Preferably, the individual compounds will be administeredsimultaneously in a combined pharmaceutical composition. Appropriatedoses of known therapeutic agents will be readily appreciated by thoseskilled in the art.

Accordingly, the pharmaceutical compositions of the present inventioninclude those that also comprise at least one additional therapeuticallyactive agent, in addition to the compound of Formula (I).

The invention further includes a compound of Formula (I) in combinationwith one or more other drug(s).

Methods of Preparing the Compounds of Formula (I)

The compounds of this invention may be made by a variety of methods,including standard chemistry in light of the present disclosure.Illustrative general synthetic methods are set out below and thenspecific compounds of the Formula (I) are prepared in the Examples.

Compounds of Formula (I) may be prepared in light of the presentdisclosure via techniques known in the art of organic synthesis,examples of which are set forth in the following synthesis schemes. Itwould be well understood by those skilled in the art in light of thepresent disclosure that in all of the schemes described below,protecting groups for sensitive or reactive groups should be employedwhere necessary in accordance with general principles of chemistry.Protecting groups can be manipulated according to standard methods oforganic synthesis (T. W. Green and P. G. M. Wuts (1991) ProtectingGroups in Organic Synthesis, John Wiley & Sons). These groups can beremoved at a convenient stage of the compound synthesis using methodsthat are readily apparent to those skilled in the art. In certain otherembodiments, a functional group presented in these schemes below can beconverted to another functional group using standard functional groupmanipulation procedures known in the art. See, for example,“Comprehensive Organic Synthesis” (B. M. Trost & I. Fleming, eds.,1991-1992).

The selection of protecting groups as well as the reaction conditionsand order of reaction steps shall be consistent with the preparation ofcompounds of Formula (I). Those skilled in the art will recognize inlight of the present disclosure whether a stereocenter exists incompounds of Formula (I). When a compound is desired as a singleenantiomer, it may be obtained by stereospecific synthesis or byresolution of the final product or any convenient intermediate.Resolution of the final product, an intermediate, or a starting materialmay be effected by any suitable method known in the art. See, forexample, Stereochemistry of Organic Compounds by E. L. Eliel, S. H.Wilen, and L. N. Mander (Wiley-Interscience, 1994).

The following solvents, reagents, protecting groups, moieties, and otherdesignations may be referred to by their abbreviations:

Me=methyl; Et=ethyl; Pr=propyl; i-Pr=isopropyl, Bu=butyl;tert-Bu=tert-butyl; Ph=phenyl, and Ac=acetyl

μL=microliters

AcOH or HOAc=acetic acid

APCI=atmospheric-pressure chemical ionization

aq=aqueous

Bn=benzyl

Boc or BOC=tert-butoxycarbonyl

Bz=benzoyl

Cbz=benzyloxycarbonyl

DAST=diethylaminosulfur trifluoride

DBU=1,8-diazabicyclo[5.4.0]undec-7-ene

DCM=dichloromethane

DDQ=2,3-Dichloro-5,6-dicyano-1,4-benzoquinone

DEA=diethylamine

DMAP=4-Dimethylaminopyridine

DIBAL=diisobutylaluminum hydride

DIAD=diisopropyl azodicarboxylate

DIEA or Hünig's Base=N,N-diisopropylethylamine

DMF=dimethylformamide

DMSO=dimethyl sulfoxide

EA=ethyl acetate

EDC=1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

EDTA=ethylenediamine tetraacetic acid

ESI=electrospray ionization

EtOAc=ethyl acetate

g=grams

h=hour

HMDS=1,1,1,3,3,3-hexamethyldisilazane

Hex=hexanes

HPLC=high-performance liquid chromatography

LDA=lithium diisopropylamide

LCMS=liquid chromatography mass spectrometry

LRMS=low resolution mass spectroscopy

min=minute

mg=milligrams

mL=milliliters

mmol=millimoles

MeOH=methanol

MPLC=medium pressure liquid chromatography

MTBE=methyl tert-butyl ether

MS=mass spectrometry

NBS=N-bromosuccinimide

NMO=4-methylmorpholine N-oxide

NMR=nuclear magnetic resonance spectroscopy

PE=petroleum ether

rac=racemic mixture

rt=room temperature (ambient, about 25° C.)

sat=saturated

SFC=supercritical fluid chromatography

TBSCl=t-butyldimethylsilyl chloride

TBS=t-butyldimethyl silyl

TEA=triethylamine (Et₃N)

TFA=trifluoroacetic acid

THF=tetrahydrofuran

TLC=thin layer chromatography

TMS=trimethylsilyl

TPAP=tetrapropylammonium perruthenate

TsOH=p-toluenesulfonic acid

General Methods

Methods for preparing compounds described herein are illustrated in thefollowing synthetic schemes. The schemes are given for the purpose ofillustrating the invention, but not for limiting the scope or spirit ofthe invention. Starting materials shown in the schemes can be obtainedfrom commercial sources or be prepared based on procedures described inthe literature.

The synthetic route illustrated in Scheme 1 is a general method forpreparing various carbamates. Reaction of a starting amine A with acarbamoylating agent of structure B where X is a leaving group whichincludes halides, electron deficient phenols, imidazole, triazoles, orother moieties well-known to those trained in the art affords the targetcarbamate C.

The reaction procedures in Scheme 1 are contemplated to be amenable topreparing a wide variety of carbamoyl-substituted tetrahydroquinolines,carbamoyl-substituted benzoxazines, carbamoyl substitutedtetrahydronaphthyridines, carbamoyl-substituted tetrahydropyridooxazinescompounds having different substituents at the R¹, R², R^(a1), R^(b),R⁴, and Cy positions. A wide variety of alcohol starting materialsnecessary to prepare the carbamoylating reagent B are commerciallyavailable or readily prepared via known methods. Furthermore, if afunctional group that is part of the R¹, R², R^(a1), R^(b), R⁴, or Cygroup would not be amenable to a reaction condition described in Scheme1, it is contemplated that the functional group can first be protectedusing standard protecting group chemistry and strategies, and then theprotecting group is removed after completing the desired synthetictransformation.

Scheme 2 illustrates a different general method for preparingcarbamates. Treatment of the amine A with phosgene, triphosgene, orother reagents known to convert aromatic or heteroaromatic amines toisocyanates, affords the isocyanate B which when treated with an alcoholC either without or with a catalyst (a base which includes but is notlimited to triethyl amine, DBU, Hunig's base, or a metal catalyst suchas a dibutyl tin dilaurate and numerous others known to those trained inthe art) affords the carbamate D.

Scheme 3 illustrates a different general method for preparingcarbamates. Treatment of the carboxylic acid A with conditions suitableto prepare an acyl azide (diphenyl phosphoryl azide, or isobutylchloroformate and sodium azide, or other similar conditions known tothose trained in the art) afford the acyl azide, which upon heatingrearranges to form the isocyanate B. Treatment of the isocyanate with analcohol C affords the carbamate D.

Scheme 4 illustrates another general method for preparing carbamates ofthe invention. Treatment of a halide or triflate (X=OTf) A underPd-mediated coupling conditions with an unsubstituted carbamate Caffords the carbamate D. The unsubstituted carbamate C can be preparedfrom alcohols B via treatment with either potassium isocyanate and acidor with sulfurisocyanatidic chloride.

Scheme 5 illustrates a general method for preparing alcohols andcarbamoylating reagents suitable for the Scheme 1 and other generalschemes below. Treatment of a ketone or aldehyde A with a Grignardreagent, R^(fs)Li, a R^(fs) metal, or a trialkylsilyl reagent (i.e.,trimethyl silyl trifluoromethane) affords the alcohol B, which can bereacted with p-nitrochloroformate, carbonyldiimide, or phosgene toafford the carbamoylating reagents.

The synthetic route in Scheme 6 is a general method for preparingvarious carbamoyl-substituted benzoxazines and aza-benzoxazinescompounds having a variety of protected aminomethyl side-chains, such ascarbamates, ureas, sulfamides etc. Reaction of nitro-aryl aniline A withan epoxide provides benzoxazine B. The nitro group in benzoxazine B canbe reduced in the presence of Boc₂O to a Boc carbamate group to provideBoc benzoxazine C. Mitsunobu reaction of benzoxazine C, followed byhydrolysis of the phthalamide provides aminomethyl benzoxazine E.Functionalization of the aminomethyl group and sulfonylation of thebenzoxazine leads to Boc-carbamate G. Removal of the Boc carbamate groupunder acidic conditions and subsequent installation of the desiredbenzoxazine carbamate affords H.

Scheme 7 shows the synthesis of 3-substituted benzoxazines andaza-benzoxazines (or pyrido oxazines). Condensation of amino phenol Awith chloro ketone B leads to imine C, which upon exhaustive reductionwith NaBH₄ affords methyl alcohol D. Bis-sulfonylation, followed byS_(N)2 displacement of the activated methyl alcohol moiety with NaN₃gives azide F. Lastly, reduction of the azide, functionalization of thecorresponding aminomethyl side-chain group, and replacing of theBoc-carbamate with a suitable carbamate yields 3-substituted benzoxazinecarbamate H.

An alternative method for preparing substituted benzoxazines andaza-benzoxazines stereoselectively [shown as (R,R,S), but not limitedto] can be seen in Scheme 8. Addition of an enolate of the oxazolidinoneA to the Boc-protected aldehyde B can afford a variety of (S,S,R)betahydroxycarboxylic acids C diastereoselectively (see J. Am. Chem.Soc. (2003) 125, 8218-8227). Protection of the alcohol moiety with asilyl group followed by a Curtius rearrangement in the presence ofbenzyl alcohol can afford the bis-carbamate D. This alcohol is added invia an SnAr displacement of the p-nitrophenyl halide of compound E, toafford the phenolic ether F. Exchange of the Boc-moiety with an SO₂Cymoiety affords the sulfonamide G, which via a palladium-mediatedintramolecular cyclization can afford the benzoxazine H. This can beconverted to the aniline I, and carbamoylated as described in the aboveschemes to afford the bis-carbamate J. Exchange of the benzoyl carbamatemoiety with an appropriate amine protecting group (R) affords the finalcompounds K. The other diastereomers can also be prepared using the sameroute, but starting with the other enantiomers of compound A and/or B.

The synthetic route illustrated in Scheme 9 is a general method forpreparing various carbamoyl-substituted tetrahydroquinoline andtetrahydronaphthyridine compounds. Nitration of A by reacting it with amixture of nitric acid and sulfuric acid provides7-nitro-tetrahydroquinoline or tetrahydronaphthyridine B. A sulfonamidegroup can be installed by reacting B with a mild base or sodium hydrideand a sulfonyl chloride (Cy-SO₂Cl) to provide sulfonamide C. The nitrogroup in compound C can be reduced to an amino group providing anilineD, which can be reacted with a carbamoylating reagent from generalScheme 5 to provide the final carbamate E.

Scheme 10 illustrates a general method for preparing dihydroquinolines.Condensation of phenylene diamine A with ethyl acetoacetate under reflux(e.g., using Conrad-Limpach conditions) provides7-amino-4-methylquinolin-2(1H)-one B. See, for example, Med. Chem Res.(2010) vol. 19, pages 193-209 for additional description of syntheticprocedures known to those trained in the art. The amino group onquinolinone B can be reacted with a carbamoylating reagent from Scheme 5to afford carbamate C. Reaction of carbamate C with mild base and asulfonyl chloride (Cy-SO₂Cl) provides dihydroquinoline D.

Scheme 11 illustrates a general method for preparing fluoro-substituted,hydroxyl-substituted, and alkoxy-substituted tetrahydroquinoline andtetrahydronaphthyridine compounds. Oxidation of A using potassiumpermanganate provides ketone B. Ketone B can be reduced to alcohol C,reacted with a fluorinating agent (such as DAST) to providedifluorotetrahydroquinoline or tetrahydronaphthyridine D, or furtheroxidized to enone E. The oxidative conversion of ketone B to E can becarried using, for example, manganese dioxide, DDQ or selenium dioxide.Reaction of E with a fluorinating agent (such as DAST) providesfluoro-dihydroquinoline or tetrahydronaphthyridine F. Finally, asdepicted below alkoxy-substituted tetrahydroquinoline ortetrahydronaphthyridine G can be prepared by reaction of alcohol C withmethanesulfonyl chloride to provide an intermediate mesylate that isreacted with an alkoxide, such as sodium methoxide, to provide G.

Scheme 12 illustrates a general method for preparingtetrahydroquinolines and tetrahydronaphthyridines having an alkylsubstituent attached to the 4-position of the bicyclic core. Amidecoupling of halo-aniline A with an acid chloride or with an carboxylicacid with a coupling reagent provides amide B. Synthetic intermediate Bis subjected to Heck Coupling conditions to provide C, which can bereduced to lactam D. Synthetic intermediate D can be converted to thecarbamate E, and subsequent reaction with the desired sulfonyl chloride,followed by reduction of the lactam moiety, provides the desiredtetrahydroquinoline or tetrahydronaphthyridine G.

The reaction procedures in Scheme 13 are contemplated to be amenable topreparing a wide variety of carbamoyl-substitutedtetrahydro-1,5-naphthyridine compounds having different substituents atthe R¹ and R³ positions. For example, numerous substituted5-bromo-3-aminopyridines are known in the literature and/or arecommercially available, such as 5-bromo-6-methyl-pyridin-3-amine,5-bromo-4-methyl-pyridin-3-amine, 5-amino-3-bromo-2-methoxylpyridine,and 5-bromo-4,6-dimethyl-pyridin-3-amine. Furthermore, if a functionalgroup that is part of R¹ or R³ would not be amenable to a reactioncondition described in Scheme 15, it is contemplated that the functionalgroup can first be protected using standard protecting group chemistryand strategies, and then the protecting group is removed aftercompleting the desired synthetic transformation. See, for example,Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis,2^(nd) ed.; Wiley: New York, 1991, for further description of protectingchemistry and strategies known to those trained in the art. In certainother embodiments, a functional group in substituent R¹ and R³ intetrahydro-1,5-naphthyridine F can be converted to another functionalgroup using standard functional group manipulation procedures known inthe art. See, for example, “Comprehensive Organic Synthesis” (B. M.Trost & I. Fleming, eds., 1991-1992).

Scheme 14 illustrates an alternative general method for preparingsubstituted 5,6,7,8-tetrahydro-1,5-naphthyridine compounds. Reduction ofhalo-nitro-pyridine A with dissolving metals provideshalo-amino-pyridine B. Exemplary dissolving metal reduction conditionsinclude the use of, for example, (1) SnCl₂ in HCl as described by Adamset al. in WO 2008/150827, or (2) Fe in HCl or NH₄Cl as described byCarroll et al. in J. Med. Chem. 2002, 45, 4755-4761 and Oalmann et al.in WO 2010/071853. Reaction of halo-amino-pyridine B with a sulphonylchloride or sulfamoyl chloride provides halo-pyridinyl sulfonamide C.Reaction of halo-pyridinyl sulfonamide C with a vinyl boronic acid orvinyl stannane provides alkene D, which can be allylated using, forexample, an allyl halide under basic conditions or an allyl alcoholunder Mitsunobu conditions to provide di-alkene E. Di-alkene E can besubjected to ring closing metathesis conditions to providedihydro-1,5-naphthyridine F. For exemplary ring closing metathesisconditions, see, for example, Mitsuhiro et al. in J. Org. Chem. 2006,71, 4255-4261. Reduction of dihydro-1,5-naphthyridine F providessaturated tetrahydro-1,5-naphthyridine G. The methyl ester ontetrahydro-1,5-naphthyridine G can be converted to a carboxylic acidunder hydrolytic conditions, and the resulting carboxylic acid issubjected to reaction conditions that facilitate Curtius rearrangement(see, for example, Ninomiya in Tetrahedron 1974, 30, 2151-2157) toprovide intermediate or final tetrahydronaphthyridinyl carbamate H. Thecarbamate functional group of an intermediate tetrahydronaphthyridinylcarbamate H can be converted to an amino group using standard carbamateprotecting group removal procedures, and the resultingamino-tetrahydronaphthyridine can be reacted with carbamoylatingreagents to provide carbamoyl-tetrahydro-1,5-naphthyridine I.

Scheme 15 illustrates a general route to providing oxygenated5,6,7,8-tetrahydro-1,5-naphthyridine compounds. Chiral osmylation ofalkene A provides diol B. For exemplary chiral osmylation procedures,see, for example, Noe et al. in Org. Reactions 2005, 66, 109. Reductionof diol B provides alcohol C. The hydroxyl group in compound C can bealkylated to provide ether D, or the hydroxyl group can be converted toother functional groups using functional group conversion proceduresknown in the art.

Scheme 16 illustrates another general procedure for preparing5,6,7,8-tetrahydro-1,5-naphthyridine compounds. Treatment ofhalo-nitro-pyridine A with a Negishi reagent under Pd-mediatedconditions provides diester B. For additional description of relatedprocedures, see, for example, Zhu et al. in J. Org. Chem. 1991, 56,1445-1453. Dissolving metal reduction of diester B with in situcyclization affords dihydro-1,5-naphthyridin-2(1H)-one C. Reaction ofdihydro-1,5-naphthyridin-2(1H)-one C with a protecting groupinstallation reagent (e.g., benzylbromide (Bn-Br)) provides protectedamide D, which after hydrolysis and in situ formation of the azide andCurtius rearrangement provides carbamate E. A substituent can beinstalled alpha to the amide group by reaction of carbamate E with baseand an electrophile (e.g., R³-halide) to providesubstituted-dihydro-1,5-naphthyridin-2(1H)-one F. Reduction ofsubstituted-dihydro-1,5-naphthyridin-2(1H)-one F can be performed byreaction with a hydride (e.g., a borane or lithium aluminum hydride) toprovide tetrahydro-1,5-naphthyridine G. Next, protecting groups (e.g.,the benzyl and carbamate protecting group) are removed and the resultingamine is reacted with carbamoylating reagents from Scheme 5 to providecarbamoyl-tetrahydro-1,5-naphthyridine I and reacted with a sulphonylchloride to provide the final tetrahydro-1,5-naphthyridine J.

Scheme 17 illustrates another procedure for preparing substitutedtetrahydro-1,5-naphthyridines. Reacting halo-nitro-pyridine A with aNegishi reagent (formed from a2-((tert-butoxycarbonyl)amino)-3-iodopropanoate) provides amino acid B.Then, amino acid B is subjected to dissolving metal reduction conditionswith in situ cyclization to provide dihydro-1,5-naphthyridin-2(1H)-oneC. Subjecting dihydro-1,5-naphthyridin-2(1H)-one C to hydrolysisconditions provides a carboxylic acid (not shown), that after in situformation of an acyl azide followed by a Curtius rearrangement providesbis-carbamate D. Selective reduction of the amide group in bis-carbamateD using borane or lithium aluminum hydride providestetrahydro-1,5-naphthyridine E. Reaction of tetrahydro-1,5-naphthyridineE with a sulphonyl chloride or sulfamoyl chloride provides sulfonamideF. Next, the benzylcarbamate protecting group is removed fromsulfonamide F to provide an amino-tetrahydro-1,5-naphthyridine (notshown) that can be subjected to carbamoylating reagents from Scheme 5 toprovide carbamoyl-tetrahydro-1,5-naphthyridine G. The remaining Bocprotecting group on carbamate-tetrahydro-1,5-naphthyridine G can beremoved by treatment with acid to provideamino-tetrahydro-1,5-naphthyridine H. It would be understood by thosetrained in the art that the amino group onamino-tetrahydro-1,5-naphthyridine H can be converted to otherfunctional groups (e.g., by reaction with an alkylating agent(s),aldehyde (reductive alkylations), acyl halide, sulphonyl chloride,isocyanate, and the like) to afford the compound I.

Scheme 18 illustrates another general method for preparing substitutedtetrahydro-1,5-naphthyridines. Carbamoylation of amino-pyridine Aprovides pyridine B, which is treated with an allylic alcohol under Heckconditions to provide compound C. For an exemplary description of suchHeck reaction conditions, see, for example, Colbon et al. in J. Org.Letters 2011, 13, 5456-5459. Subjecting Compound C to reductivecyclization conditions followed by treatment with a sulphonyl chlorideprovides sulfonamide-tetrahydro-1,5-naphthyridine D.

Scheme 19 illustrates a general method for preparing2-substituted-2,3-dihydro-1H-pyrido[2,3-b]oxazines. Reaction ofchloro-pyridine A with hydroxy-ketone B provides nitro-pyridyl ether C.Exhaustive reduction (e.g., using Raney Nickel) of compound C providesamino-dihydro-1H-pyrido[2,3-b]oxazine D. Carbamoylation ofpyrido[2,3-b]oxazine D provides pyrido[2,3-b]oxazine E, which is treatedwith a sulphonyl chloride to afford final compound F.

Scheme 20 illustrates a general method for preparingsubstituted-2,3-dihydro-1H-pyrido[2,3-b]oxazines. Reactingchloro-pyridine A with protected hydroxyketone (or a protectedhydroxyaldehyde) B provides an aryl-alkyl ether intermediate (not shown)that upon acid hydrolysis provides dinitropyridyl-ketone (ordinitropyridyl-aldehyde) C. Exhaustive reduction (e.g., using RaneyNickel) of compound C provides amino-dihydro-1H-pyrido[2,3-b]oxazine D.Carbamoylation of the amino group in compound D affordsdihydro-1H-pyrido[2,3-b]oxazine E, which is treated with a sulphonylchloride or a sulfamoyl chloride to afford the final compound F.

In embodiments where it is desirable to prepare pyrido-oxazines F inchiral form, a protected chiral hydroxyketone B can be used as startingmaterial.

Scheme 21 illustrates another general method for preparingsubstituted-2,3-dihydro-1H-pyrido[2,3-b]oxazines. Reaction ofhalo-pyridine A with a 2-hydroxyester provides nitro-carboxypyridine B.Subjecting nitro-carboxypyridine B to dissolving metal reductionconditions with in situ cyclization affords1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one C. Subjecting1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one C to hydrolysis conditionsprovides a carboxylic acid (not shown), that after in situ formation ofan acyl azide followed by a Curtius rearrangement provides carbamate D.Selective reduction of the amide group in carbamate D using borane orlithium aluminum hydride provides dihydro-1H-pyrido[2,3-b]oxazine E.Reaction of dihydro-1H-pyrido[2,3-b]oxazine E with a sulphonyl chlorideprovides sulfonamide F. Next, the carbamate protecting group is removedfrom sulfonamide F to provide amino-dihydro-1H-pyrido[2,3-b]oxazine Gthat can be carbamoylated as described in Scheme 5 to providedihydro-1H-pyrido[2,3-b]oxazine H.

Scheme 23 illustrates an alternate general method for preparingsubstituted-2,3-dihydro-1H-pyrido[2,3-b]oxazines. Reaction ofhalo-nitropyridine A with a hydroxyalkyl-epoxide provides nitro-pyridylether B. Subjecting nitro-pyridyl ether B to dissolving metal reductionconditions with in situ cyclization affords a bicyclic alkoxideintermediate (not shown) that is reacted with an alcohol protectinggroup reagent (e.g., a trialkylsilylchloride or with an alkyl halide ifthe final target is an ether) to provide bicyclic ether C. Reaction ofbicyclic ether C with a sulphonyl chloride or sulfamoyl chlorideprovides sulfonamide-pyrido-oxazine D. The methyl ester onsulfonamide-pyrido-oxazine D can be converted to a carboxylic acid usinghydrolytic conditions to provide an intermediate carboxylic acidcompound (not shown), that is converted to an acyl azide followed by aCurtius rearrangement to provide carbamate E. The carbamate protectinggroup may be removed using standard deprotection conditions to provide abicyclic amine (not shown) that can be carbamoylated to form5,6,7,8-tetrahydro-1,5-naphthyridine F. In embodiments, where R^(IX) isa protecting group (e.g., a trialkylsilyl group), R^(IX) may be removedusing standard deprotection conditions (e.g., usingtetra-n-butylammonium fluoride) to provide alcohol G.

Scheme 24 shows the general synthetic route to tetrahydroquinolinecarboxylic acids and acid derivatives as analogues of the benzoxazinecore. Halogenation of readily available quinoline B and subsequent Heckreaction affords alpha,beta-unsubstituted ester C. Partial reduction ofthe quinoline moiety, in addition to reduction of the nitro and doublebond groups in the presence of Boc₂O, affords Boc-carbamate D. CompoundD can subsequently be elaborated to the desired tetrahydroquinolinecarboxylic acid derivative H using similar chemistry as described above.

EXAMPLES

The invention now being generally described will be more readilyunderstood by reference to the following examples, which are includedfor purposes of illustration of certain aspects and embodiments of thepresent invention, and are not intended to limit the invention. Startingmaterials useful for preparing the compounds of Formula (I) can beobtained from commercial sources or are readily prepared fromcommercially available materials using transformations which are knownto those of skill in the art of organic chemistry.

Example 1—Synthesis of (R)-tert-butyl(2-(hydroxymethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(1)

The title compound was prepared according to the procedures describedbelow.

Part I—Synthesis of2-[[(2S)-3-chloro-2-hydroxypropyl]amino]-4-nitrophenol

A solution of 2-amino-4-nitrophenol (250.0 g, 1.62 mol) and(2S)-2-(chloromethyl)oxirane (330.0 g, 3.57 mol) in ethanol:water (2500mL:25 mL) was stirred for twelve hours at 60° C. in an oil bath. Theresulting mixture was cooled and concentrated to afford2-[[(2S)-3-chloro-2-hydroxypropyl]amino]-4-nitrophenol as a brown oil.

Part II—Synthesis of[(2R)-6-nitro-3,4-dihydro-2H-1,4-benzoxazin-2-yl]methanol

A solution of 2-[[(2S)-3-chloro-2-hydroxypropyl]amino]-4-nitrophenol(400 g, 1.62 mol) in ethanol (2.5 L) and potassium carbonate (134.5 g,973 mmol) was stirred for twelve hours at 90° C. in an oil bath. Themixture was filtered and the filtrate was concentrated. The residue wasdiluted with water (1.5 L) and extracted three times with ethyl acetate(1 L). The combined organic layers were washed with brine, dried(Na₂SO₄), and concentrated. The residue was purified via MPLC oversilica gel eluting with ethyl acetate/petroleum ether (1:1) to afford[(2R)-6-nitro-3,4-dihydro-2H-1,4-benzoxazin-2-yl]methanol as a redsolid.

Part III—Synthesis of((R)-2-hydroxymethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-carbamic acidtert-butyl ester

The atmosphere above a solution of[(2R)-6-nitro-3,4-dihydro-2H-1,4-benzoxazin-2-yl]methanol (137 g, 652mmol), palladium on carbon (13.7 g) and di-tert-butyl dicarbonate (157g, 717 mmol) in methanol (1400 mL) was exchanged with hydrogen. Theresulting solution was stirred for twelve hours at room temperature. Themixture was filtered, and the filtrate was concentrated. The crudeproduct was purified by re-crystallization from ether to afford((R)-2-hydroxymethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-carbamic acidtert-butyl ester as an off-white solid. LRMS (ESI) calculated forC₁₄H₂₀N₂O₄ 280: Found: 225 (M-C₄H₈+H)⁺; 281 (M+H)⁺. ¹H NMR (300 MHz,CDCl₃): δ 6.92 (s, 1H), 6.71 (d, J=8.7 Hz, 1H), 6.41 (dd, J=8.7, 2.4 Hz,1H), 6.26 (s, 1H), 4.20-4.21 (m, 1H), 3.76-3.86 (m, 2H), 3.26-3.35 (m,2H), 1.53 (s, 9H).

Part IV—Synthesis of (R)-tert-butyl(2-(hydroxymethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a stirred solution of (R)-tert-butyl(2-(hydroxymethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(2.0 g, 7.1 mmol) in pyridine (14 mL) and anhydrous THF (7 mL) was addeddropwise 3-(trifluoromethyl) benzene-1-sulfonyl chloride (2.6 g, 10.6mmol) at room temperature. After an hour, the resulting mixture wasconcentrated and the residue was partitioned between ethyl acetate (30mL) and water (30 mL). The aqueous layer was extracted three times withethyl acetate. The combined organic layers were dried (MgSO₄) andconcentrated. The residue was purified by column chromatography onsilica gel eluting with petroleum ether:ethyl acetate (5:1) to give(R)-tert-butyl(2-(hydroxymethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamateas a white solid. ¹H NMR (400 MHz, CDCl₃) δ 1.52 (s, 10H) 1.88 (t, J=6.4Hz, 1H) 3.39-3.46 (m, 1H) 3.57 (dd, J=9.2, 2.4 Hz, 1H) 3.65-3.81 (m, 2H)4.29 (dd, J=14.0, 2.0 Hz, 1H) 6.44 (br s, 1H) 6.78 (d, J=9.2 Hz, 1H)7.17 (d, J=7.6 Hz, 1H) 7.59-7.68 (m, 1H) 7.76 (d, J=2.0 Hz, 1H) 7.84 (d,J=8.0 Hz, 1H) 7.90 (d, J=8.0 Hz, 1H) 8.05 (s, 1H). LRMS (ESI) calculatedfor C₂₁H₂₄F₃N₂O₆S (M+H)⁺: 489, Found: 489.

Example 2—Preparation of additional (R)-tert-butyl(2-(hydroxymethyl)-4-(optionally substituted aryl orheteroaryl-sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamates

The compounds in Table 1 below were prepared based on the experimentalprocedures described in Example 1 and elsewhere in the detaileddescription, and can be achieved by one of skill in the art in light ofthe present disclosure. Starting materials can be obtained fromcommercial sources or readily prepared from commercially availablematerials.

TABLE 1 Ex. No. Structure Name Observed m/z 2A

(R)-tert-butyl (4-((5-bromo-2- chloropyridin-3-yl)sulfonyl-2-(hydroxymethyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 556  (M + Na)⁺ 2B

(R)-4-((6-((tert- butoxycarbonyl)amino)-2- (hydroxymethyl)-2H-benzo[b][1,4]oxazin-4(3H)- yl)sulfonyl)-1-(difluoromethyl)-3-methyl-1H-pyrazol-2-e 419.2 (M-tBu + H)⁺ 2C

[(R)-4-(3-chloro-benzenesulfonyl)-2- hydroxymethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamic acid tert-butyl ester 399.0 (M-tBu + H)⁺2D

(R)-tert-butyl (4-((5-bromopyridin-3-yl)sulfonyl)-2-(hydroxymethyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 500   (M + H)⁺ 2E

(R)-tert-butyl (2-(hydroxymethyl)-4- ((1-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 369  (M-tBu + H)⁺ 2F

(R)-tert-butyl (2-(hydroxymethyl)-4-((3-(methylsulfonyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin- 6-yl)carbamate 443.0 (M-tBu + H)⁺ 2G

(R)-tert-butyl (4-((2-chloro-5- methylpyridin-3-yl)sulfonyl)-2-(hydroxymethyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 470  (M + H)⁺ 2H

(R)-tert-butyl (4-((3- cyanophenyl)sulfonyl)-2-(hydroxymethyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 390.0(M-tBu + H)⁺

Example 3—Synthesis of (R)-tert-butyl(2-(hydroxymethyl)-4-((5-methyl-2-oxo-1,2-dihydropyridin-3-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(3)

A solution of (R)-tert-butyl(4-((2-chloro-5-methylpyridin-3-yl)sulfonyl)-2-(hydroxymethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(102 mg, 0.217 mmol), andchloro[2-(di-tert-butylphosphino)-2′,4′,6′-triisopropyl-1,1′-biphenyl][2-(2-aminoethyl)phenyl)]palladium(II)(22.36 mg, 0.033 mmol) in p-dioxane (1085 μL) and water (1085 μl) waspurged thoroughly with argon. Potassium hydroxide (48.7 mg, 0.868 mmol)was then added and the reaction was sealed and heated at 80° C. for twohours. The mixture was cooled, diluted with ethyl acetate, washed twicewith aqueous sodium hydrogen carbonate and then with brine. The aqueouslayers were back extracted once with ethyl acetate. The combined organiclayers were dried (Na₂SO₄) and concentrated. The residue was purified byMPLC eluting with a gradient of 1-10% methanol in dichloromethane toafford (R)-tert-butyl(2-(hydroxymethyl)-4-((5-methyl-2-oxo-1,2-dihydropyridin-3-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamateas a yellow solid. ¹H NMR (600 MHz, DMSO-d6) δ 12.17 (s, 1H), 9.11 (s,1H), 8.19 (d, J=2.2 Hz, 1H), 7.74 (s, 1H), 7.52 (s, 1H), 6.76 (dd,J=1.9, 8.8 Hz, 1H), 6.69 (d, J=8.8 Hz, 1H), 5.01 (t, J=5.6 Hz, 1H), 4.38(dd, J=1.8, 13.5 Hz, 1H), 4.08-4.02 (m, 1H), 3.64-3.56 (m, 1H),3.57-3.51 (m, 1H), 3.44 (dd, J=9.1, 13.3 Hz, 1H), 2.09 (s, 3H), 1.42 (s,9H). LRMS (ESI) calculated for C₂₀H₂₅N₃O₇S (M+H)⁺: 452, Found: 452.

Example 4—Synthesis of (R)-tert-butyl(4-((4-fluorophenyl)sulfonyl)-2-(2-hydroxypropan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamateand (S)-tert-butyl(4-((4-fluorophenyl)sulfonyl)-2-(2-hydroxypropan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(Example Nos. 4A and 4B)

The title compound was prepared according to the procedures describedbelow.

Part I—Synthesis of ethyl4-((4-fluorophenyl)sulfonyl)-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate

A mixture of ethyl6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate (4.5 g, 17.9mmol), 4-fluorobenzene-1-sulfonyl chloride (4.52 g, 23.3 mmol) andpyridine (7.07 g, 89.5 mmol) in THF (100 mL) was stirred at 60° C. forfifteen hours. The reaction mixture was concentrated, and the residuewas partitioned between dichloromethane (100 mL) and water (100 mL). Theaqueous layer was extracted twice with dichloromethane, and the combinedorganic layers were washed with brine, dried (Na₂SO₄), and concentrated.The residue was purified by column chromatography on silica gel elutingwith petroleum ether:ethyl acetate (5:1) to afford ethyl4-((4-fluorophenyl)sulfonyl)-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylateas a yellow solid. LRMS (ESI) calculated for C₁₇H₁₆FN₂O₇S (M+H)⁺: 411,Found: 411.

Part II—Synthesis of ethyl6-((tert-butoxycarbonyl)amino)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate

To a solution of ethyl4-((4-fluorophenyl)sulfonyl)-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate(5.0 g, 12.2 mmol) and di-tert-butyl dicarbonate (2.92 g, 13.4 mmol) inethanol (100 mL) was added Pd/C (1.0 g, 10% wt) under argon. Thesuspension was degassed under vacuo and purged with hydrogen threetimes. The mixture was stirred under the pressure of 40 psi hydrogen at30° C. for four hours. The suspension was filtered through a pad ofCELITE and the filter cake was washed with ethanol (20 mL). The combinedfiltrates were concentrated to dryness to give ethyl6-((tert-butoxycarbonyl)amino)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylateas a yellow solid. LRMS (ESI) calculated for C₂₂H₂₆FN₂O₇S (M+H)⁺: 481,Found: 481.

Part III—Synthesis of (R)-tert-butyl(4-((4-fluorophenyl)sulfonyl)-2-(2-hydroxypropan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamateand (S)-tert-butyl (4-((4-fluorophenyl)sulfonyl)-2-(2-hydroxypropan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a stirred solution of ethyl6-((tert-butoxycarbonyl)amino)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylate(5.5 g, 11.5 mmol) in anhydrous THF (70 mL) was added a 3M solution ofmethyl magnesium bromide (38.3 mL, 115 mmol) in ethyl ether at −78° C.,and the resultant mixture was warmed to 25° C. and stirred for anadditional hour. The reaction mixture was poured into saturated ammoniumchloride (500 mL), and extracted twice with dichloromethane (500 mLeach). The combined organic layers were dried (Na₂SO₄), andconcentrated. The residue was purified by column chromatography onsilica gel eluting with petroleum ether:ethyl acetate (3:1) to afford aracemic mixture of the title compounds as a white solid, which waschirally separated by SFC (Instrument: Thar SFC 350; Column: AD 300mm*50 mm, 10 um; Mobile phase: A: Supercritical CO₂, B: MeOH (0.1%NH₃.H₂O), A:B=65:35 at 240 mL/min; Column Temp: 38° C.; Nozzle Pressure:100 Bar; Nozzle Temp: 60° C.; Evaporator Temp: 20° C.; Trimmer Temp: 25°C.; Wavelength: 220 nm) to afford the two isomers.

Isomer 1: (R)-tert-butyl(4-((4-fluorophenyl)sulfonyl)-2-(2-hydroxypropan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate¹H NMR (400 MHz, CDCl₃) δ 7.62-7.75 (m, 3H), 7.32 (br. s., 1H), 7.15 (t,J=8.4 Hz, 2H), 6.81 (d, J=9.2 Hz, 1H), 6.44 (br. s., 1H), 4.38 (dd,J=2.0, 14.4 Hz, 1H), 3.19 (dd, J=10.4, 14.4 Hz, 1H), 3.03 (dd, J=1.6,10.4 Hz, 1H), 1.53 (s, 9H), 1.20 (d, J=12.4 Hz, 6H). LRMS (ESI)calculated for C₂₂H₂₈FN₂O₆S (M+H)⁺: 467, Found: 467.

Isomer 2: (S)-tert-butyl(4-((4-fluorophenyl)sulfonyl)-2-(2-hydroxypropan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate.¹H NMR (400 MHz, CDCl₃) δ 7.65-7.74 (m, 3H), 7.33 (br. s, 1H), 7.15 (t,J=8.4 Hz, 2H), 6.81 (d, J=8.4 Hz, 1H), 6.44 (br. s, 1H), 4.38 (dd,J=2.0, 14.0 Hz, 1H), 3.19 (dd, J=10.4, 14.0 Hz, 1H), 3.03 (dd, J=1.6,10.4 Hz, 1H), 1.53 (s, 9H), 1.20 (d, J=12.4 Hz, 6H). LRMS (ESI)calculated for C₂₂H₂₈FN₂O₆S (M+H)⁺: 467, Found: 467.

Example 5—Preparation of (R and S)-1,1,1-trifluoro-2-methylpropan-2-yl4-(3,4-difluorophenylsulfonyl)-2-(2,2,2-trifluoroacetyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-ylcarbamate(5)

Step 1-Preparation of1-(4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2,2,2-trifluoroethanone

To a solution of(R)-4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylicacid (7.5 g, 23.85 mmol) in dichloromethane (150 mL) and 2 drops of DMFat 0° C. was added oxalyl chloride (12 mL). The mixture was allowed towarm to room temperature and was stirred for an additional two hours.The mixture was concentrated. To a solution of the resulting residue indichloromethane (150 mL) at 0° C. was added trifluoroacetic anhydride(19.5 mL, 143.1 mmol) followed by slow addition of pyridine (15 mL). Themixture was allowed to warm to room temperature and stirred for 24hours. The mixture was cooled in an ice bath, ice water was added intothe mixture slowly, and the mixture was stirred at room temperature foran additional hour. The mixture was extracted twice withdichloromethane. The combined organic phases were washed with 1 N HCl,brine, dried (Na₂SO₄) and concentrated. The residue was purified bycolumn chromatography on silica gel eluting with petroleum ether:ethylacetate (20:1 to 10:1) to give the title compound as a red oil. LCMS(ESI): calculated for C₁₇H₁₃F₃N₂O₄ (M+H)⁺: 367, found: (M+H₂O+H)⁺ 385.

Step 2—Preparation of1-(6-amino-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2,2,2-trifluoroethanone

To a solution of1-(4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2,2,2-trifluoroethanone(1.0 g, 2.73 mmol) in ethyl acetate (30 mL) purged with nitrogen wasadded Pd/C (1 g). The atmosphere above the solution was exchanged with aballoon of hydrogen and was stirred at room temperature for 16 hours.The mixture was filtered through a pad of CELITE and the filtrate wasconcentrated to afford the title compound as a dark-white solid whichwas used without any further purification. LCMS (ESI): calculated forC₁₀H₉F₃N₂O₂ (M+H)⁺: 247, found: 247.

Step 3-Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl2-(2,2,2-trifluoroacetyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-ylcarbamate

To a solution of1-(6-amino-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2,2,2-trifluoroethanone(2.8 g, 23.6 mmol) and 1,1,1-trifluoro-2-methylpropan-2-yl1H-imidazole-1-carboxylate (2.78 g, 25.9 mmol) in DMSO (28 mL) was addedconcentrated HCl (1.2 mL, 13.44 mmol) and the mixture was stirred at 70°C. for 5 hours. The mixture was diluted with saturated NaHCO₃ andextracted three times with ethyl acetate. The combined organic layerswere washed with brine, dried (Na₂SO₄), and concentrated. The residuewas purified via MPLC to afford an off-white solid (dichloromethane:ethyl acetate=20:1-10:1). LCMS (ESI): calculated for C₁₅H₁₄F₆N₂O₄(M+H)⁺: 401, found (M+H₂O+H)⁺: 419.

Step 4—Preparation of (R and S)-1,1,1-trifluoro-2-methylpropan-2-yl4-(3,4-difluorophenylsulfonyl)-2-(2,2,2-trifluoroacetyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-ylcarbamate

To a room temperature solution of 1,1,1-trifluoro-2-methylpropan-2-yl2-(2,2,2-trifluoroacetyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-ylcarbamate(400 mg, 1.0 mmol) in THF (6 mL) and pyridine (2 mL) was added3,4-difluorobenzene-1-sulfonyl chloride (425 mg, 2.0 mmol) and themixture was stirred overnight. The mixture was diluted with 1 N of HCl(final mixture had a pH=3) and was extracted twice with ethyl acetate.The combined organic phase was washed with brine, dried (Na₂SO₄) andconcentrated. The residue was purified by column chromatography onsilica gel eluting with a gradient of petroleum ether:ethyl acetate of10:1 to 3:1 to afford the title compound as a yellow oil. LCMS (ESI):calculated for C₂₁H₁₆F₈N₂O₆S (M+H)⁺: 577, found (M+H₂O+Na)⁺: 617; ¹H-NMR(400 MHz, CD₃OD) δ 7.92 (br s, 1H), 7.61-7.65 (m, 1H), 7.42-7.50 (m,2H), 7.09-7.10 (m, 1H), 6.75-6.81 (m, 1H), 4.44-4.55 (m, 1H), 3.45-3.47(m, 1H), 3.24-3.25 (m, 2H), 1.73 (s, 6H).

Example 6—Preparation of additional 1,1,1-trifluoro-2-methylpropan-2-ylbenzoxazines

The compound in Table 2 below is prepared based on the experimentalprocedures described in Example 5, and can be achieved by one of skillin the art in light of the present disclosure.

TABLE 2 Ex. Observed No. Structure Name m/z 6A

(R and S)-1,1,1-trifluoro-2- methylpropan-2-yl (4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2- (2,2,2-trifluoroacetyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 633 (M + H₂O + Na)⁺ 6B

(R and S)-1,1,1-trifluoro-2- methylpropan-2-yl (4-((4-fluorophenyl)sulfonyl)-2-(2,2,2- trifluoroacetyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 559 (M + H)+

Example 7—Synthesis of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(aminomethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(7)

The title compound was prepared according to the procedures describedbelow.

Part I—Synthesis of (S)-tert-butyl(2-(((benzyloxy)carbonyl)aminomethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To (S)-tert-butyl(2-(aminomethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (2.5g, 8.95 mmol), N,N′-diisopropylethylamine (3.91 mL, 22.4 mmol), anddichloromethane (44.7 mL) was added dropwise benzyl chloroformate (1.28mL, 8.95 mmol) over five minutes at 0° C. The reaction was warmed toroom temperature and stirred for four hours. The mixture was diluted insaturated sodium bicarbonate and extracted with isopropanol/chloroform(1:3 v/v). The combined organic layers were washed with brine, dried(MgSO₄) and concentrated to afford (S)-tert-butyl(2-(((benzyloxy)carbonyl)aminomethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate.

Part II—Synthesis of (S)-tert-butyl(2-(((benzyloxy)carbonyl)aminomethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

A mixture of (S)-tert-butyl(2-(((benzyloxy)carbonyl)aminomethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(7.4 g, 17.90 mmol), pyridine (89 mL), and 4-fluorobenzene-1-sulfonylchloride (6.97 g, 35.8 mmol) was heated at 60° C. for two hours. Themixture was partitioned between isopropanol chloroform and saturatedsodium bicarbonate. The organic layer was washed with brine, dried(MgSO₄) and concentrated to afford (S)-tert-butyl(2-(((benzyloxy)carbonyl)aminomethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate.

Part III—Synthesis of (S)-benzyl((6-amino-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl)carbamate

A mixture of (S)-tert-butyl(2-(((benzyloxy)carbonyl)aminomethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(10 g, 17.49 mmol) and 4M HCl in p-dioxane (109 mL, 437 mmol) wasstirred at room temperature for 30 minutes and concentrated to afford(S)-benzyl((6-amino-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl)carbamate.

Part IV—Synthesis of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(((benzyloxy)carbonyl)aminomethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (S)-benzyl((6-amino-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl)carbamate(4.00 g, 7.87 mmol), dichloromethane (39.4 mL), and triethyl amine (6.59mL, 47.2 mmol) was added 4-nitrophenyl(1,1,1-trifluoro-2-methylpropan-2-yl) carbonate (5.77 g, 19.69 mmol) and4-N,N-dimethylaminopyridine (0.192 g, 1.575 mmol). The mixture wasstirred at room temperature overnight and poured into saturated sodiumbicarbonate. The mixture was extracted with isopropanol/chloroform. Thecombined organic layers were washed with 1N NaOH, dried (MgSO₄) andconcentrated. The residue was purified via chromatography eluting with agradient of (0-100% ethyl acetate/hexanes) to afford(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(((benzyloxy)carbonyl)aminomethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate.

Part V—Synthesis of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(aminomethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

A solution of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(((benzyloxy)carbonyl)aminomethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(750 mg, 1.20 mmol) and methanol (12 mL) was purged with nitrogen.Palladium 10% on carbon (76 mg, 0.072 mmol) was added. The atmospherewas exchanged with hydrogen at one atmosphere and stirred for fourhours. The mixture was filtered through CELITE. The filtrate wasconcentrated to afford(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(aminomethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamateas a white solid. ¹H NMR: (300 MHz, CDCl₃): δ 9.81 (1H, s), 8.00 (2H,s), 7.92 (1H, s), 7.84 (2H, m), 7.46 (2H, m), 7.22 (1H, d, J=9.7 Hz),6.80 (1H, d, J=8.24 Hz), 4.41 (1H, dd, J=11.79 Hz, 2.66 Hz), 3.72 (1H,m), 3.34 (1H, m), 3.20 (1H, m), 2.96 (1H, m), 1.70 (6H, s). LRMS (ESI)calculated for C₂₀H₂₁F₄N₃O₅S (M+H)⁺: 492, Found 492.1.

Example 8—Synthesis of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(((benzyloxy)carbonyl)aminomethyl)-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(8)

To a mixture of (S)-benzyl((6-amino-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl)carbamatehydrochloride (4.80 g, 8.85 mmol), dichloromethane (88 mL), and triethylamine (7.40 mL, 53.1 mmol) was added 4-nitrophenyl(1,1,1-trifluoro-2-methylpropan-2-yl) carbonate (5.71 g, 19.47 mmol).The mixture was stirred for one day at room temperature. The mixture waspartitioned between isopropanol/chloroform (1:3, v/v) and saturatedsodium bicarbonate. The organic layer was washed with 1N NaOH, dried(MgSO₄) and concentrated. The residue was purified by MPLC eluting witha gradient of 0-100% ethyl acetate/hexanes to afford(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(((benzyloxy)carbonyl)aminomethyl)-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamateas a white solid. LRMS (ESI) calculated for C₂₈H₂₆ClF₄N₃O₇SNa (M+Na): ⁺682, Found: 682.2. ¹H NMR: (300 MHz, CDCl₃) δ 9.77 (1H, s), 7.98 (1H,m), 7.90 (1H, s), 7.70 (1H, m), 7.61 (1H, t, J=10.13 Hz), 7.53 (1H, t,J=6.51 Hz), 7.35 (3H, m), 7.31 (1H, m), 7.12 (1H, d, J=9.41 Hz), 6.77(1H, d, J=7.95 Hz), 5.04 (2H, m), 4.31 (1H, m), 3.53 (1H, m), 3.26 (3H,m), 3.19 (1H, m), 1.70 (6H, m).

Example 9—Synthesis of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-2-((3-(tetrahydro-2H-pyran-4-yl)ureido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(9)

A solution of(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(aminomethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(30 mg, 0.061 mmol), 4-isocyanatotetrahydro-2H-pyran (31.0 mg, 0.244mmol), triethyl amine (34.0 μL, 0.244 mmol), and dichloromethane (610μL) was stirred overnight. The mixture was partitioned between saturatedsodium bicarbonate and dichloromethane. The organic layer was dried(MgSO₄) and concentrated. The residue was dissolved in DMSO (1.5 mL),filtered, and purified by reverse phase chromatography to afford(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-2-((3-(tetrahydro-2H-pyran-4-yl)ureido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate.LRMS (ESI) calculated for C₂₆H₃₁F₄N₄O₇S (M+H): ⁺: 619, Found: 619. ¹HNMR: (300 MHz, CDCl3) δ 9.76 (1H, s), 7.90 (1H, s), 7.73 (2H, m), 7.38(2H, t, J=8.58 Hz), 7.18 (1H, d, J=10.13 Hz), 6.76 (1H, d, J=9.36 Hz),6.03 (1H, d, J=6.96 Hz), 5.97 (1H, m), 4.26 (1H, m), 3.78 (3H, m), 3.33(5H, m), 3.14 (2H, m), 1.69 (7H, m), 1.30 (2H, m).

Example 10—Additional Ureas and Carbamates of Aminobenzoxazines

The urea and bis-carbamate compounds in Table 3 below were preparedbased on the experimental procedures described in Examples 7, 8, and 9and elsewhere in the detailed description, and can be achieved by one ofskill in the art in light of the present disclosure.

TABLE 3 Ex. Observed No. Structure Name m/z 10A

(S)-tert-butyl (2- (((benzyloxy)carbonyl)aminomethyl)- 4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-6-yl)carbamate 628.2 (M + Na)⁺ 10B

(S)-1,1,1-trifluoro-2-methylpropan-2- yl (2-(((benzyloxy)carbonyl)aminomethyl)- 4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 626.3 (M + H)⁺ 10C

(S)-tert-butyl (2- (((methoxy)carbonyl)aminomethyl)-4-((4-fluorophenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 440.1 (M-tBu + H)⁺ 10D

(S)-tert-butyl (4-((4- fluorophenyl)sulfonyl)-2-((3-methylureido)methyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-6- yl)carbamate439.0 (M-tBu + H)⁺ 10E

(S)-1,1,1-trifluoro-2-methylpropan-2- yl(2-((3-cyclopropylureido)methyl)- 4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 575.2 (M + H)⁺ 10F

(S)-1,1,1-trifluoro-2-methylpropan-2- yl(2-((3-cyclobutylureido)methyl)-4- ((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 589.1 (M + H)⁺ 10G

(S)-1,1,1-trifluoro-2-methylpropan-2- yl(2-((3-(tert-butyl)ureido)methyl)- 4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 591.1 (M + H)⁺ 10H

(S)-1,1,1-trifluoro-2-methylpropan-2- yl(4-((4-fluorophenyl)sulfonyl)-2- ((3-isopropylureido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 577.1 (M + H)⁺ 10i

(S)-1,1,1-trifluoro-2-methylpropan-2- yl(4-((4-fluorophenyl)sulfonyl)-2- ((3-(thiophen-3-yl)ureido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin- 6-yl)carbamate 617.1 (M + H)⁺ 10J

(S)-1,1,1-trifluoro-2-methylpropan-2- yl(2-((3-ethylureido)methyl)-4-((4- fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 563.1 (M + H)⁺ 10K

(S)-1,1,1-trifluoro-2-methylpropan-2- yl(2-((3-cyclohexylureido)methyl)-4- ((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 617.0 (M + H)⁺

Example 11—Synthesis of(R)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-4-fluorophenyl)sulfonyl)-2-((5-methyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(11)

Part 1—Synthesis of (R)-tert-butyl(2-((5-methyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (R)-tert-butyl(2-(hydroxymethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(200 mg, 0.713 mmol), triphenylphosphine (187 mg, 0.713 mmol),2-methyl-1,2,5-thiadiazolidine 1,1-dioxide (97 mg, 0.713 mmol), andtoluene (3567 μL) was added diisopropyldiazodicarboxylate (146 μL, 0.749mmol). The reaction was stirred at 50° C. for two hours. The mixture waspartitioned between ethyl acetate and saturated NaHCO₃. The organiclayer was washed with brine, dried (MgSO₄), and concentrated. Theresidue was purified by MPLC eluting with a gradient of 0-100% ethylacetate in hexanes to afford the title compound: LCMS (ESI) calculatedfor C₁₇H₂₇N₄O₅S (M+H)⁺: 399, Found: 399.

Part 2—Synthesis of (R)-tert-butyl(4-((3-chloro-4-fluorophenyl)sulfonyl)-2-((5-methyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

A solution of (R)-tert-butyl(2-((5-methyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(148.5 mg, 0.373 mmol), 3-chloro-4-fluorobenzene-1-sulfonyl chloride(171 mg, 0.745 mmol), and pyridine (1863 μL) was heated at 50° C.overnight. The mixture was cooled, and partitioned between ethyl acetateand saturated NaHCO₃. The organic layer was washed with brine, dried(MgSO₄), and concentrated. The residue was purified via MPLC elutingwith a gradient of 0-100% ethyl acetate in hexanes to afford the titlecompound: LCMS (ESI) calculated for C₁₉H₂₀ClFN₄O₇S₂ (M-tBu+H)⁺: 535,Found: 535.

Part 3—Synthesis of(R)-2-((6-amino-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl)-5-methyl-1,2,5-thiadiazolidine1,1-dioxide

A solution of (R)-tert-butyl(4-((3-chloro-4-fluorophenyl)sulfonyl)-2-(5-methyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(208 mg, 0.352 mmol), HCl (1760 μL, 7.04 mmol), and THF (1760 μL) washeated at 50° C. for three days. The mixture was cooled and concentratedto afford the title compound: LCMS (ESI) calculated for C₁₈H₂₁ClFN₄O₅S₂(M+H)⁺: 491, Found: 491.

Part 4—Synthesis of (R)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-4-fluorophenyl)sulfonyl)-2-((5-methyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

A solution of(R)-2-((6-amino-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl)-5-methyl-1,2,5-thiadiazolidine1,1-dioxide (173 mg, 0.352 mmol), 1,1,1-trifluoro-2-methylpropan-2-yl1H-imidazole-1-carboxylate (133 mg, 0.599 mmol), and DMF (1762 μL) washeated at 100° C. for two hours. The reaction was partitioned betweenethyl acetate and saturated NaHCO₃. The organic layer was washed withbrine, dried (MgSO₄), and concentrated. The residue was purified viaMPLC eluting with a gradient of 0-100% ethyl acetate in hexanes toafford the title compound: LCMS (ESI) calculated for C₂₃H₂₆ClF₄N₄O₇S₂(M+H)⁺: 645, Found: 645. ¹H NMR: (300 MHz, CDCl₃): δ 9.78 (1H, s), 8.07(1H, d, J=7.19 Hz), 7.92 (1H, s), 7.75 (1H, m), 7.64 (1H, t, J=10.79Hz), 7.14 (1H, d, J=7.2 Hz), 6.80 (1H, d, J=10.79 Hz), 4.39 (1H, d,J=14.32 Hz), 3.71 (1H, m), 3.63 (1H, t, J=7.16 Hz), 3.20 (2H, m), 2.60(3H, s), 1.73 (1H, m), 1.70 (6H, s), 1.52 (1H, m), 1.31 (2H, m).

Example 12—Synthesis of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-2-(((N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(12)

To a stirred mixture of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(aminomethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(50 mg, 0.102 mmol), methylsulfamoyl chloride (13.18 mg, 0.102 mmol),and dichloromethane (1017 μL was added N,N′-diisopropylethylamine (26.7μL, 0.153 mmol) at room temperature. After twenty hours, the mixture waspartitioned between ethyl acetate and saturated sodium bicarbonate. Theorganic layer was dried (MgSO₄) and concentrated. The residue wasdissolved in DMSO (1.5 mL), filtered and purified by reverse phasechromatography to afford the title compound. LRMS (ESI) calculated forC₂₁H₂₅F₄N₄O₇S₂ (M+H)+: 585, Found: 585. ¹H NMR (300 MHz, CDCl₃) δ 9.77(1H, s), 7.90 (1H, s), 7.77 (2H, m), 7.41 (2H, t, J=7.99 Hz), 7.19 (2H,m), 6.79 (1H, m), 6.76 (1H, d, J=8.71 Hz), 4.38 (1H, m), 3.52 (1H, m),3.22 (1H, m), 3.00 (2H, m), 2.41 (3H, m), 1.69 (6H, m).

Example 13—Additional Sulfamides of Aminobenzoxazines

The compounds in Table 4 below were prepared based on the experimentalprocedures described in Examples 11 and 12 and elsewhere in the detaileddescription utilizing the appropriate sulfamoyl halide, and can beachieved by one of skill in the art in light of the present disclosure.

TABLE 4 Ex. Observed No. Structure Name m/z 13A

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((4-fluorophenyl)sulfonyl)-2-((morpholine-4-sulfonamido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 641.3 (M + H)⁺ 13B

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(((N,N-diethylsulfamoyl)amino)methyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 627.2 (M + H)⁺ 13C

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(((N,N-dimethylsulfamoyl)amino)methyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 599.1 (M + H)⁺ 13D

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((4-fluorophenyl)sulfonyl)-2-((piperidine-1-sulfonamido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 639 (M + H)⁺ 13E

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((4-fluorophenyl)sulfonyl)-2-((pyrrolidine-1-sulfonamido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 625 (M + H)⁺ 13F

1,1,1-trifluoro-2-methylpropan-2-yl((2S)-4-((4-fluorophenyl)sulfonyl)-2- ((2-methylpiperidine-1-sulfonamido)methyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate653 (M + H)⁺ 13G

1,1,1-trifluoro-2-methylpropan-2-yl ((2S)-2-((2,6-dimethylmorpholine-4-sulfonamido)methyl)-4-((4- fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 669 (M + H)⁺ 13H

(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-2-((4- methylpiperidine-1-sulfonamido)methyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate653 (M + H)⁺ 13i

1,1,1-trifluoro-2-methylpropan-2-yl((2S)-4-((4-fluorophenyl)sulfonyl)-2- ((2-methylmorpholine-4-sulfonamido)methyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate655 (M + H)⁺ 13J

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(((N-cyclopropyl-N-methylsulfamoyl)amino)methyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 625 (M + H)⁺ 13K

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(((N-cyclopentyl-N-methylsulfamoyl)amino)methyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 653 (M + H)⁺ 13L

(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-2-(((N- methyl-N-(2,2,2-trifluoroethyl)sulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 667 (M + H)⁺ 13M

(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-4-fluorophenyl)sulfonyl)-2-(((N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 619.5 (M + H)⁺ 13N

(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-4-fluorophenyl)sulfonyl)-2-((piperidine-1-sulfonamido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 673 (M + H)⁺ 13o

1,1,1-trifluoro-2-methylpropan-2-yl ((2S)-4-((3-chloro-4-fluorophenyl)sulfonyl)-2-((2- methylpiperidine-1-sulfonamido)methyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate687 (M + H)⁺ 13P

1,1,1-trifluoro-2-methylpropan-2-yl ((2S)-4-((3-chloro-4-fluorophenyl)sulfonyl)-2-((2- methylmorpholine-4-sulfonamido)methyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate689 (M + H)⁺ 13Q

(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-4-fluorophenyl)sulfonyl)- 2-(((N-methyl-N-(2,2,2-trifluoroethyl)sulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 701 (M + H)⁺ 13R

(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-4-fluorophenyl)sulfonyl)- 2-(((N-isobutyl-N-methylsulfamoyl)amino)methyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 675 (M + H)⁺ 13S

1,1,1-trifluoro-2-methylpropan-2-yl ((2S)-4-((3-chloro-4-fluorophenyl)sulfonyl)-2-((3- methylpyrrolidine-1-sulfonamido)methyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate688 (M + H)⁺ 13T

(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-4-fluorophenyl)sulfonyl)-2-(((N-ethylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 633.0 (M + H)⁺ 13U

(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-4-fluorophenyl)sulfonyl)- 2-(((N-isopropylsulfamoyl)amino)methyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 647.0 (M + H)⁺ 13V

(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(((N-ethylsulfamoyl)amino)methyl)- 4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 599.1 (M + H)⁺ 13W

(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-2-(((N-isopropylsulfamoyl)amino)methyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 613.1 (M + H)⁺ 13X

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(((N-(tert-butyl)sulfamoyl)amino)methyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 627.1 (M + H)⁺ 13Y

(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3,4-difluorophenyl)sulfonyl)-2- (((N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 603.1 (M + H)⁺ 13Z

(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-ethoxy-1-ethyl-1H-pyrazol-4- yl)sulfonyl)-2-(((N-methylsulfamoyl)amino)methyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 629.1 (M + H)⁺ 13AA

(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((1-ethyl-3-methyl-1H-pyrazol-4- yl)sulfonyl)-2-(((N-methylsulfamoyl)amino)methyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 599.1 (M + H)⁺ 13AB

(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4- yl)sulfonyl)-2-(((N-methylsulfamoyl)amino)methyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 619.1 (M + H)⁺ 13AC

(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-(2,2-difluoroethoxy)-1-ethyl-1H- pyrazol-4-yl)sulfonyl)-2-(((N-methylsulfamoyl)amino)methyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 665.1 (M + H)⁺ 13AD

(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((1-(2,2-difluoroethyl)-3-ethoxy-1H- pyrazol-4-yl)sulfonyl)-2-(((N-methylsulfamoyl)amino)methyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 665.1 (M + H)⁺ 13AE

(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((1-(difluoromethyl)-3-methyl-1H- pyrazol-4-yl)sulfonyl)-2-(((N-methylsulfamoyl)amino)methyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 621.1 (M + H)⁺ 13AF

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((2-methoxy-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)sulfonyl)-2-(((N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 627.1 (M + H)⁺ 13AG

2,2,2-trifluoro-1,1-dimethylethyl [(2S)-4- {[1-(difluoromethyl)-3-(2-hydroxyethoxy)-1H-pyrazol-4- yl]sulfonyl}-2-{[(methylsulfamoyl)amino]methyl}- 3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbamate 667 (M + H)⁺

Example 14—Synthesis of (R)-tert-butyl(2-((pyridin-2-ylthio)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(14)

To(R)-(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methylmethanesulfonate (150 mg, 0.265 mmol) and cesium carbonate (431 mg, 1.32mmol) in DMF (1 mL) at room temperature was added pyridine-2-thiol (147mg, 1.32 mmol) and the mixture was stirred at room temperature for 16hours. The reaction mixture was diluted with ethyl acetate, washed withsaturated aqueous NaHCO₃, water, brine, dried (Na₂SO₄) and concentrated.The residue was purified by silica gel chromatography eluting with agradient of ethyl acetate/hexane (0˜25%) to give (R)-tert-butyl(2-((pyridin-2-ylthio)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamateas white solid. LRMS (ESI) calculated for C₂₆H₂₆F₃N₃O₅S₂ (M+H)⁺: 582,Found 582. ¹H NMR (600 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.41 (dd, J=39.2,4.0 Hz, 1H), 8.05-7.72 (m, 4H), 7.65-7.56 (m, 2H), 7.37-7.19 (m, 1H),7.19-6.97 (m, 2H), 6.71 (d, J=8.9 Hz, 1H), 4.40 (dd, J=14.2, 2.2 Hz,1H), 3.60 (s, 1H), 3.45-3.38 (m, 2H), 3.15-3.20 (m, 1H) 1.43 (s, 9H).

Example 15—Preparation of Additional (R)-tert-butyl (2-((thioalkyl orthioaryl orthioheteroaryl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamates

The compounds in Table 5 below were prepared based on the experimentalprocedures described in Example 14 and elsewhere in the detaileddescription using the appropriate thiol in place of pyridine-2-thiol,and can be achieved by one of skill in the art in light of the presentdisclosure.

TABLE 5 Ex. No. Structure Name Observed m/z 15A

(R)-tert-butyl (2- ((cyclopentylthio)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 595.0 (M + Na)⁺ 15B

(R)-tert-butyl (2-((benzylthio)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 617.0 (M + Na)⁺ 15C

(R)-tert-butyl (2-((tert-butylthio)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 583.0 (M + Na)⁺ 15D

(R)-tert-butyl (2-(((4,5-dimethyl-1H- imidazol-2-yl)thio)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 599.1 (M + H)⁺ 15E

(R)-tert-butyl (2-((phenylthio)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 525.0 (M-tBu + H)⁺15F

(R)-tert-butyl (2-((methylthio)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 540.8 (M + Na)⁺

Example 16—Synthesis of (R)-tert-butyl(2-((pyridin-2-ylsulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(16)

To a solution of (R)-tert-butyl(2-((pyridin-2-ylthio)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(100 mg, 0.172 mmol) in dichloromethane (5 mL) was addedmeta-chloroperbenzoic acid (148 mg, 0.860 mmol) and the mixture wasstirred at room temperature for three hours. The mixture wasconcentrated and purified by silica gel chromatography using a gradientof ethyl acetate/hexane (0˜50%), to give (R)-tert-butyl(2-((pyridin-2-ylsulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamateas a white solid. ¹H NMR (600 MHz, DMSO-d6) δ 9.24 (s, 1H), 8.69 (d,J=4.7 Hz, 1H), 8.19-7.68 (m, 7H), 6.89 (d, J=8.9 Hz, 1H), 5.99 (d, J=8.9Hz, 1H), 4.40 (dd, J=14.1, 2.3 Hz, 1H), 4.01-3.79 (m, 3H), 3.50 (dd,J=14.2, 9.0 Hz, 1H), 1.42 (s, 9H).

Example 17—Preparation of additional (2-((alkyl or aryl or heteroarylsulfonyl)methyl)-benzoxazines

The compounds in Table 6 below were prepared based on the experimentalprocedures described in Example 16 and elsewhere in the detaileddescription, and can be achieved by one of skill in the art in light ofthe present disclosure.

TABLE 6 Ex. No. Structure Name Observed m/z 17A

(R)-tert-butyl (2-((tert- butylsulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 615.0 (M + Na)⁺ 17B

(R)-tert-butyl (2-(((4,5-dimethyl-1H-imidazol-2-yl)sulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 631.0 (M + H)⁺ 17C

(R)-tert-butyl (2- ((phenylsulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 635.0 (M + Na)⁺ 17D

(R)-tert-butyl (2- ((cyclopentylsulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 549.2 (M-tBu + H)⁺ 17E

(R)-tert-butyl (2- ((benzylsulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 644.2 (M + NH₄)⁺ 17F

(R)-tert-butyl (2- ((methylsulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 572.8 (M + Na)⁺

Example 18—Synthesis of (R)-tert-butyl(2-((pyridin-2-ylsulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(18)

The title compound was prepared according to the procedures describedbelow.

Part I—Synthesis of (R)-tert-butyl(2-((benzylthio)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a suspension of sodium hydride (78 mg, 1.942 mmol) in DMF (1 mL) atroom temperature was added phenylmethanethiol (0.233 mL, 1.942 mmol) andthe mixture was stirred at room temperature for ten minutes. Then asolution of(R)-(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methylmethanesulfonate (550 mg, 0.971 mmol) in DMF (4 mL) was added and thestirring continued at room temperature overnight. The reaction mixturewas diluted with ethyl acetate, washed with bleach, water and brinesubsequently, then dried (Na₂SO₄) and concentrated. The residue waspurified on silica chromatograph (40 g) and eluted with a gradient ofethyl acetate/hexane (0˜25%) to give (R)-tert-butyl(2-((benzylthio)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamateas light yellow solid. LRMS (ESI) calculated for C₂₈H₂₉F₃N₂O₅S₂ (M+H)⁺:595, Found: 539 (M-tBu+H)⁺ and 617 (M+Na)⁺.

Part II—Synthesis of (R)-tert-butyl(2-((chlorosulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (R)-tert-butyl(2-((benzylthio)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(50 mg, 0.084 mmol) in acetic acid (1 mL)/water (0.33 mL) at roomtemperature was added N-chlorosuccinimide (33.7 mg, 0.252 mg) and themixture was stirred at room temperature for 2.5 hours. The mixture wasdiluted with ethyl acetate, washed with saturated aqueous sodiumthiosulfate, water and brine, then dried (Na₂SO₄) and concentrated togive the crude product (R)-tert-butyl(2-((chlorosulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate.LRMS (ESI) calculated for C₂₁H₂₂ClF₃N₂O₇S₂ (M+H)⁺: 571, Found: 515(M-tBu+H)⁺ and 593 (M+Na)⁺.

Part III—Synthesis of (R)-tert-butyl(2-((pyridin-2-ylsulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (R)-tert-butyl(2-((chlorosulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamatemate(50 mg, 0.084 mmol) in dichloromethane (50 mg, 0.088 mmol) at roomtemperature was added methylamine hydrochloride (0.219 mL, 0.438 mmol)followed by triethyl amine (0.037 mL, 0.263 mmol) and the mixture wasstirred at room temperature for an hour. The solvent was concentratedand the residue was purified via MPLC eluting with an ethylacetate/hexanes gradient (0-50%) to afford (R)-tert-butyl(2-((pyridin-2-ylsulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate.LRMS (ESI) calculated for C₂₂H₂₆F₃N₃O₇S₂ (M+H)⁺: 566, Found: 510(M-tBu)⁺ and 588 (M+Na)⁺. ¹H NMR (600 MHz, DMSO-d6) δ 9.28 (s, 1H), 8.04(dd, J=33.5, 7.6 Hz, 4H), 7.82 (t, J=8.0 Hz, 1H), 7.03 (dd, J=13.1, 7.3Hz, 2H), 6.74 (d, J=8.9 Hz, 1H), 4.49 (d, J=14.0 Hz, 1H), 3.84 (s, 1H),3.51-3.37 (m, 2H), 3.29 (dd, J=14.7, 7.1 Hz, 1H), 2.50 (s, 3H), 1.44 (s,9H).

Example 19—Preparation of Additional Reverse 2-alkyl SulfonamideBenzoxazines

The compounds in Table 7 below were prepared based on the experimentalprocedures described in Example 18 and elsewhere in the detaileddescription, and can be achieved by one of skill in the art in light ofthe present disclosure.

TABLE 7 Ex. No. Structure Name Observed m/z 19A

(R)-tert-butyl (2-((N- cyclopropylsulfamoyl)methyl)-4-((3-(trifluoromethyl) phenyl)sulfonyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 535.9 (M-tBu + H)⁺ 19B

(R)-tert-butyl (2-((N-(2,2,2- trifluoroethyl)sulfamoyl) methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 655.9 (M + Na)⁺ 19C

(R)-tert-butyl (2- ((morpholinosulfonyl) methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 566.0 (M-tBu + H)⁺ 19D

(R)-tert-butyl (2-((N- ethylsulfamoyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 602.0 (M + Na)⁺ 19E

(R)-tert-butyl (2-((N,N- dimethylsulfamoyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 523.9 (M-tBu + H)⁺

Example 20—Synthesis of1,1,1-trifluoro-2-methylpropan-2-yl(S)-(4-((3-ethoxy-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(20)

Part 1—Synthesis of 1-ethyl-1,2-dihydro-3H-pyrazol-3-one

To methyl 2-chloroprop-2-enoate (5 mL, 49.8 mmol) in anhydroustetrahydrofuran (75 mL) was added ethylhydrazine oxalate (11.2 g, 74.7mmol) followed by triethylamine (13.9 mL, 99.6 mmol). The reaction wasstirred at ambient temperature overnight. The solids were filtered off,then the filtrates were concentrated. The residue was purified by columnchromatography eluting with a gradient of methanol in dichloromethane.The pure fractions were combined and concentrated in vacuo to yield thetitle compound.

Part 2—Synthesis of 3-ethoxy-1-ethyl-1H-pyrazole

To a solution of 1-ethyl-1,2-dihydro-3H-pyrazol-3-one (1.55 g, 13.8mmol) in N,N-dimethylformamide (15 mL) was added potassium carbonate(3.8 g, 27.6 mmol) followed by ethyl bromide (2.1 mL, 27.6 mmol). Thereaction was stirred at ambient temperature for 3 hours. The solutionwas diluted with ethyl acetate, washed with water, brine, dried withsodium sulfate, filtered and concentrated in vacuo to yield the titlecompound.

Part 3—Synthesis of 3-Ethoxy-1-ethyl-1H-pyrazole-4-sulfonyl chloride

To 3-ethoxy-1-ethyl-1H-pyrazole (3.14 g, 22.4 mmol) in chloroform (25mL) at 0° C. was added chlorosulfonic acid (15 mL, 224 mmol) dropwise.The resulting solution was stirred for 3 hours at 70° C. The solutionwas cooled in an ice bath and then quenched by pouring into ice water.The resulting suspension was extracted with dichloromethane and thecombined organic layers were dried over anhydrous sodium sulfate andconcentrated under vacuum to yield the title compound as an oil.

Part 4—Synthesis of Methyl (S)-2-(4-bromo-2-nitrophenoxy)propanoate

To a solution of 5-bromo-2-fluoronitrobenzene (5.4 g, 24.5 mmol) intetrahydrofuran (50 mL) at 0° C. was added (S)-lactic acid methyl ester(3.1 g, 29.4 mmol) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (4.4mL, 26.9 mmol). The cooling bath was removed and reaction was stirred atambient temperature overnight. The solution was partitioned betweenethyl acetate and water, washed with water, brine, dried with sodiumsulfate, filtered and concentrated in the presence of silica. Theresidue was purified by column chromatography eluting with a gradient of0-60% ethyl acetate in hexanes. The pure fractions were combined andconcentrated in vacuo to yield the title compound.

Part 5—Synthesis of(S)-6-Bromo-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one

To methyl (S)-2-(4-bromo-2-nitrophenoxy)propanoate (2.4 g, 7.9 mmol) inacetic acid (30 mL) was added powdered iron (2.2 g, 39.5 mmol) and thereaction was heated to 70° C. for 2 hours. The warm suspension wasfiltered through CELITE, and washed with ethyl acetate. The filtrateswere partitioned between ethyl acetate and water, washed with water,brine, dried with sodium sulfate, filtered and concentrated in vacuo toyield the title compound.

Part 6—Synthesis of(S)-6-Bromo-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine

To a solution of (S)-6-bromo-2-methyl-2H-benzo[b][1,4]oxazin-3(4H)-one(1.55 g, 6.4 mmol) in anhydrous tetrahydrofuran (20 mL) under a nitrogenatmosphere at ambient temperature was carefully added borane-methylsulfide complex (2.56 mL, 25.6 mmol). The reaction was then refluxed for90 minutes, cooled in an ice bath and quenched with methanol (20 mL).The suspension was next heated to reflux for 20 minutes, thenconcentrated in vacuo. The residue was partitioned between ethyl acetateand water, washed with brine, dried with sodium sulfate, filtered andconcentrated in vacuo to yield the title compound.

Part 7—Synthesis of(S)-6-Bromo-4-((3-ethoxy-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine

A mixture of (S)-6-bromo-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine(0.5 g, 2.2 mmol), 3-ethoxy-1-ethyl-1H-pyrazole-4-sulfonyl chloride(0.63 g, 2.6 mmol) and pyridine (8 mL) was stirred at 70° C. overnight.The solution was cooled, diluted with ethyl acetate, washed with 10%citric acid, brine, dried (Na₂SO₄). To the suspension was addedactivated charcoal and the suspension was slurried. The mixture wasfiltered through CELITE and concentrated. The residue was purified bycolumn chromatography eluting with a gradient of ethyl acetate inhexanes to yield the title compound.

Part 8—Synthesis of 1,1,1-Trifluoro-2-methylpropan-2-yl(S)-(4-((3-ethoxy-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

In toluene (4 mL) and water (1 mL) was combined(S)-6-bromo-4-((3-ethoxy-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine(0.2 g, 0.47 mmol),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (22 mg, 0.046mmol), tert-butyl carbamate (0.11 g, 0.93 mmol) and tripotassiumphosphate (0.3 g, 1.4 mmol) followed by the addition oftris(dibenzylideneacetone)dipalladium(0) (21 mg, 0.046 mmol) and heatedat 100° C. overnight. The cooled solution was partitioned between ethylacetate and water, washed with brine, dried (Na₂SO₄), and concentrated.The mixture was purified by column chromatography eluting with agradient of ethyl acetate in hexanes. To the intermediate was added wasadded 4M hydrogen chloride in dioxane (3 mL) and the result was stirredat ambient temperature for 1 hour. The resulting suspension wasconcentrated. The residue was redissolved in N,N-dimethylformamide (2mL) and combined with (2,2,2-trifluoro-1,1-dimethyl-ethyl)imidazole-1-carboxylate (0.097 g, 0.44 mmol). The mixture was heated to100° C. in the microwave for 2 hours. The cooled solution waspartitioned between ethyl acetate and water, washed with brine, dried(Na₂SO₄), and concentrated. The residue was purified by columnchromatography eluting with a gradient of 70-100% ethyl acetate inhexanes to afford the title compound. LCMS (ESI) calculated forC₂₁H₂₈F₃N₄O₆S (M+H)⁺: 521, Found: 521.

Example 21—Synthesis of [(2S,3S and2R,3R)-4-(3-cyano-benzenesulfonyl)-2-hydroxymethyl-3-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamicacid 2,2-dimethyl-propyl ester (21)

The title compound was prepared according to the procedures describedbelow.

Part I—Synthesis ofN-(but-3-en-2-yl)-3-cyano-N-(2-fluoro-5-nitrophenyl)-benzenesulfonamide

To a mixture of 3-cyano-N-(2-fluoro-5-nitro-phenyl)-benzenesulfonamide(2.8 g, 8.7 mmol), 3-buten-2-ol (0.626 g, 8.8 mmol) andtriphenylphosphine was added diisopropyldiazodicarboxylate (2.28 g, 9.6mmol) in THF (50 mL) dropwise at 0° C. After this addition, the mixturewas warmed to room temperature and stirred overnight. The solvent wasremoved and the resulting residue purified by silica gel chromatography(dichloromethane) to provideN-(but-3-en-2-yl)-3-cyano-N-(2-fluoro-5-nitrophenyl) benzenesulfonamide.LRMS (ESI) calculated for C₁₇H₁₆FN₃O₄S (M+H)⁺: 376, Found: 376.2.

Part II—Synthesis of3-cyano-N-(2,3-dihydroxy-1-methyl-propyl)-N-(2-fluoro-5-nitro-phenyl)-benzenesulfonamide

To a mixture of3-cyano-N-(2-fluoro-5-nitro-phenyl)-N-(1-methyl-allyl)-benzenesulfonamide(2.6 g, 6.9 mmol), N-methylmorpholine N-oxide (0.97 g, 8.3 mmol) inacetone (20 mL) and water (40 mL) was added osmium tetroxide (0.3 g).The mixture was stirred overnight at room temperature and diluted withwater (50 mL). White precipitate was filtered, washed with water andhexanes to provide a mixture of diastereomers of3-cyano-N-(2,3-dihydroxy-1-methyl-propyl)-N-(2-fluoro-5-nitro-phenyl)-benzenesulfonamide.LRMS (ESI) calculated for C₁₇H₁₇FN₃O₆S (M+H)⁺: 410, Found 410.3.

Part III—Synthesis of 3-((2S,3S and2R,3R)-2-hydroxymethyl-3-methyl-6-nitro-2,3-dihydro-benzo[1,4]oxazine-4-sulfonyl)-benzonitrile

A mixture of 3-((2S,3S and2R,3R)-2-hydroxymethyl-3-methyl-6-nitro-2,3-dihydro-benzo[1,4]oxazine-4-sulfonyl)-benzonitrile(2.5 g, 6.4 mmol), sodium hydride (0.56 g, 22.4 mmol) in THF (100 mL)was heated to reflux for three days. The mixture was cooled to 0° C. andquenched with 2N HCl, diluted with ethyl acetate, washed with water,saturated sodium bicarbonate, and concentrated. The residue was purifiedby silica gel chromatography (hexanes/ethyl acetate, 1.5/1) to provide3-((2S,3S and2R,3R)-2-hydroxymethyl-3-methyl-6-nitro-2,3-dihydro-benzo[1,4]oxazine-4-sulfonyl)-benzonitrile.LRMS (ESI) calculated for C₁₇H₁₆N₃O₄S (M+H)⁺: 390, Found: 390.1.

Part IV—Synthesis of 3-((2S,3S and2R,3R)-6-amino-2-hydroxymethyl-3-methyl-2,3-dihydro-benzo[1,4]oxazine-4-sulfonyl)-benzonitrile

A mixture of 3-((2S,3S and2R,3R)-2-hydroxymethyl-3-methyl-6-nitro-2,3-dihydro-benzo[1,4]oxazine-4-sulfonyl)-benzonitrile(2.5 g, 6.11 mmol), iron (1.0 g) in dioxane (50 mL) and 6N HCl (20 mL)was heated to reflux for three hours. After the mixture was cooled,saturated sodium bicarbonate and ethyl acetate (200 mL) were added. Thelayers were partitioned and the organic layer was washed with brine andseparated, dried (Na₂SO₄) and concentrated. The residue waschromatographed on silica gel to give desired product. LRMS (ESI)calculated for C₁₇H₁₈N₃O₂S (M+H)⁺: 360, Found: 360.3.

Part V—Synthesis of [(2S,3S and2R,3R)-4-(3-cyano-benzenesulfonyl)-2-hydroxymethyl-3-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamicacid 2,2-dimethyl-propyl ester

3-((2S,3S and2R,3R)-6-Amino-2-hydroxymethyl-3-methyl-2,3-dihydro-benzo[1,4]oxazine-4-sulfonyl)-benzonitrile(89.8 mg, 0.25 mmol) was treated with neopentyl chloroformate by theprocedures described above to give the title compound. LRMS (ESI)calculated for C₂₃H₂₈N₃O₆S (M+H)⁺: 474, Found: 474.

Example 22—Synthesis of (S and R)-1,1,1-trifluoro-2-methylpropan-2-yl4-(4-fluorophenylsulfonyl)-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-ylcarbamate(Example Nos. 22A and 22B)

Step 1—Preparation of 3-methyl-6-nitro-2H-benzo[b][1,4]oxazine

A mixture of 1-chloropropan-2-one (3.4 g, 30 mmol) and K₂CO₃ (8.3 g, 60mmol) in acetone (100 mL) was stirred for 10 minutes at roomtemperature. Then 2-amino-4-nitrophenol (5 g, 30 mmol) was added and thereaction mixture was stirred for 12 hours at 80° C. The reaction mixturewas cooled to 20° C., filtered, concentrated in vacuo and purified bycrystallization with MeOH/petroleum ether (10:1) to afford the titlecompound as a yellow solid. LCMS (ESI): calculated for C₉H₈N₂O₃ [M+H]⁺:193, found: 193.

Step 2—Preparation of3-methyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine

To a solution of 3-methyl-6-nitro-2H-benzo[b][1,4]oxazine (300 mg, 1.568mmol) in ethanol (10 mL) was added NaBH₄ (71 mg, 1.87 mmol). The mixturewas stirred at room temperature for an hour. The reaction was quenchedwith water and extracted three times with EtOAc (50 mL each). Thecombined organic layers were washed with brine, dried (Na₂SO₄), filteredand concentrated to afford the title compound as a yellow solid. LCMS(ESI): calculated for C₉H₁₀N₂O₃(M+H)⁺: 195, found: 195.

Step 3—Preparation of4-((4-fluorophenyl)sulfonyl)-3-methyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine

To a solution of 3-methyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine(300 mg, 1.55 mmol) in pyridine (4 mL) was added4-fluorobenzene-1-sulfonyl chloride (1.5 g, 7.73 mmol). The reaction wasstirred at 100° C. for 12 hours and diluted with water (10 mL). Themixture was extracted three times with ethyl acetate (50 mL each). Thecombined organic layers were dried (Na₂SO₄) and concentrated. Theresidue was crystallized with 1% methanol in ethyl acetate to give thetitle compound. LCMS (ESI): calculated for C₁₅H₁₃FN₂O₅S (M+H)⁺: 353,found: 353.

Step 4—Preparation of4-((4-fluorophenyl)sulfonyl)-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-amine

The atmosphere above a solution of4-((4-fluorophenyl)sulfonyl)-3-methyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine(250 mg, 0.71 mmol) in ethyl acetate (50 mL) was purged with nitrogenand 10% Pd/C (0.3 g) was added. The atmosphere was then replaced withhydrogen and stirred at 25° C. for 12 hours. The mixture was filteredthrough a CELITE pad, the pad was washed with ethyl acetate, and thecombined filtrates were concentrated to afford the title compound as ayellow solid. LCMS (ESI): calculated for C₁₅H₁₅FN₂O₃S (M+H)⁺: 323,found: 323.

Step 5—Preparation of (S and R)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

A mixture of 4-nitrophenyl (1,1,1-trifluoro-2-methylpropan-2-yl)carbonate (136 mg, 0.46 mmol) and4-((4-fluorophenyl)sulfonyl)-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-amine(100 mg, 0.31 mmol) in N,N-diisopropylethylamine (1.5 mL) was heated at100° C. for 16 hours. The reaction mixture was cooled and diluted with 1M HCl (20 mL). The mixture was extracted three times with EtOAc (50 mLeach). The combined organic layers were washed with brine, dried(Na₂SO₄), and concentrated. The residue was purified by prep-TLC elutingwith petroleum ether:ethyl acetate (3:1) to afford the title compound asa yellow solid, which was further separated by SFC (Column: ChiralpakAD-3 150×4.6 mm I.D., 3 um Mobile phase: methanol (0.05% DEA) in CO₂from 5% to 40% Flow rate: 2.5 mL/min Wavelength: 220 nm) to give twoisomers. LCMS (ESI): calculated for C₂₀H₂₀F₄N₂O₅S (M+H)⁺: 477, found:477.

Example 23—Synthesis of (R and S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-3-(hydroxymethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(Example Nos. 23A and 23B)

Step 1—Preparation ofN-(2-(allyloxy)-5-nitrophenyl)-4-fluorobenzenesulfonamide

To a solution of NaH (417 mg, 9.55 mmol) in THF (5 mL) was addedprop-2-en-1-ol (554 mg, 9.55 mmol) in THF (5 mL), and the reactionmixture was stirred at 0° C. for 20 minutes. Then4-fluoro-N-(2-fluoro-5-nitrophenyl)benzenesulfonamide (1.0 g, 3.18 mmol)in THF (10 mL) was added to the reaction mixture and the resultingmixture was stirred at 0° C. for 3 hours. The reaction was quenched with1 N HCl (10 mL). The mixture was partitioned between and ethyl acetateand water. The organic layer was washed with brine, dried (Na₂SO₄) andconcentrated. The residue was purified by silica gel columnchromatography eluting with petroleum ether:ethyl acetate (4:1) toafford the title compound.

Step 2—Preparation of 4-fluoro-N-(5-nitro-2-(oxiran-2-ylmethoxy)phenyl)benzenesulfonamide

A mixture of N-(2-(allyloxy)-5-nitrophenyl)-4-fluorobenzenesulfonamide(600 mg, 1.7 mmol) and m-CPBA (441 mg, 2.55 mmol) in dichloroethane (15mL) was stirred at 90° C. overnight. The mixture was cooled andconcentrated. The residue was partitioned between water and ethylacetate. The organic layer was washed with brine, dried (Na₂SO₄) andconcentrated. The residue was purified by silica gel columnchromatography eluting with petroleum ether:ethyl acetate (2:1) toafford the title compound.

Step 3—Preparation of(4-((4-fluorophenyl)sulfonyl)-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)methanol

Potassium carbonate (150 mg, 1.08 mmol) was added to4-fluoro-N-(5-nitro-2-(oxiran-2-ylmethoxy) phenyl)benzenesulfonamide(100 mg, 0.27 mmol) in acetonitrile (2 mL). The reaction mixture washeated at 120° C. by microwave irradiation for 40 minutes. The reactionmixture was diluted with water, and extracted three times with ethylacetate. The combined organic layers were washed with brine, dried(Na₂SO₄) and concentrated. The residue was purified by prep-TLC elutingwith petroleum ether:ethyl acetate (1:1) to afford the title compound.

Step 4—Preparation of(4-((4-fluorophenyl)sulfonyl)-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)methylacetate

A mixture of(4-((4-fluorophenyl)sulfonyl)-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)methanol(170 mg, 0.46 mmol), triethylamine (140 mg, 1.38 mmol) and acetylchloride (73 mg, 0.93 mmol) in dichloromethane (2 mL) was stirred atroom temperature for 2 hours. The mixture was diluted with water, andextracted twice with ethyl acetate. The combined organic layers werewashed with brine, dried (Na₂SO₄) and concentrated to afford the titlecompound as a yellow solid.

Step 5—Preparation of(6-amino-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)methylacetate

A mixture of(4-((4-fluorophenyl)sulfonyl)-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)methylacetate (190 mg, 0.46 mmol) and 10% palladium on carbon (50 mg) in ethylacetate (5 mL) was stirred under a hydrogen atmosphere (15 psi)overnight. The mixture was filtered through CELITE, the filter pad waswashed with ethyl acetate, and the combined filtrates were concentratedto afford the title compound. LCMS (ESI): calculated for C₁₇H₁₇FN₂O₅S(M+H)⁺: 381, found: 381.

Step 6—Preparation of(4-((4-fluorophenyl)sulfonyl)-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)methylacetate

A mixture of(6-amino-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)methylacetate (120 mg, 0.32 mmol) and 1,1,1-trifluoro-2-methylpropan-2-yl1H-imidazole-1-carboxylate (120 mg, 0.54 mmol) in DMSO (3 mL) wasstirred at 80° C. overnight. The mixture was diluted with water,extracted with twice with ethyl acetate and the combined organic layerswere washed with brine, dried (Na₂SO₄) and concentrated. The residue waspurified by silica gel column chromatography eluting with petroleumether:ethyl acetate (5:1) to afford the title compound. LCMS (ESI):calculated for C₂₂H₂₂F₄N₂O₇S (M+H)⁺: 535, found: 535.

Step 7—Preparation of (R and S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-3-(hydroxymethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

A mixture of(4-((4-fluorophenyl)sulfonyl)-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-3-yl)methylacetate (140 mg, 0.26 mmol) and potassium carbonate (310 mg, 2.23 mmol)in MeOH (4.5 mL) and water (0.5 mL) was stirred at room temperature forfour hours. The reaction mixture was diluted with water, extracted withtwice with ethyl acetate and the combined organic layers were washedwith brine, dried (Na₂SO₄) and concentrated. The residue was purified bysilica gel column chromatography eluting with petroleum ether:ethylacetate (5:1) to afford the title compound, which was further separatedby SFC (Column: Chiralpak AD-H 250×4.6 mm I.D., 5 um Mobile phase:methanol (0.05% DEA) in CO₂ from 5% to 40% Flow rate: 2.35 mL/minWavelength: 220 nm) to give two isomers. LCMS (ESI): calculated forC₂₀H₂₀F₄N₂O₆S (M+H)⁺: 493, found: 493; ¹H NMR (400 MHz, CDCl₃) δ 7.82(br s, 1H), 7.68 (dd, J=4.8, 8.4 Hz, 2H), 7.23 (d, J=8.0 Hz, 1H), 7.14(t, J=8.4 Hz, 2H), 6.81 (br s, 1H), 6.76 (d, J=8.4 Hz, 1H), 4.39 (t,J=6.4 Hz, 1H), 4.13 (d, J=11.8 Hz, 1H), 3.62-3.68 (m, 1H), 3.51-3.58 (m,1H), 3.18 (dd, J=2.4, 11.6 Hz, 1H), 1.76 (s, 6H).

Example 24—Synthesis of[(S)-4-(3-cyano-benzenesulfonyl)-2-(2,4-dioxo-oxazolidin-3-ylmethyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamicacid tert-butyl ester (24)

To a solution of triphenylphosphine (1.2 g, 4.7 mmol) in tetrahydrofuran(7.5 mL) at 0° C. was added diisopropylazodicarboxylate (0.9 mL, 4.7mmol). After fifteen minutes,[(R)-4-(3-cyano-benzenesulfonyl)-2-hydroxymethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamicacid tert-butyl ester (1.4 g, 3.1 mmol) and 2,4-oxazolidinedione (0.3 g,3.1 mmol) in tetrahydrofuran (7.5 mL) was added dropwise. After theaddition was complete the mixture was allowed to warm to roomtemperature. The mixture was stirred an additional three hours, andpartitioned between dichloromethane and 1 N HCl. The organic layer wasdried (Na₂SO₄) and concentrated to afford[(S)-4-(3-cyano-benzenesulfonyl)-2-(2,4-dioxo-oxazolidin-3-ylmethyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamicacid tert-butyl ester. LCMS ESI calculated for C₂₄H₂₅N₄O₈S (M+H)⁺: 529,Found: 529.

Example 25—Preparation of Additional Carbamates of2-((2,4-dioxooxazolidin-3-yl)methyl)-benzoxazines

The compounds in Table 8 below were prepared based on the experimentalprocedures described in Example 24 and elsewhere in the detaileddescription, and can be achieved by one of skill in the art in light ofthe present disclosure.

TABLE 8 Ex. Observed No. Structure Name m/z 25A

(1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl ((S)-4-((3-cyanophenyl)sulfonyl)-2-((2,4-dioxooxazolidin-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 584.2 (M + Na)⁺ 25B

(S)-neopentyl (4-((3- cyanophenyl)sulfonyl)-2-((2,4-dioxooxazolidin-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 543.1 (M + H)⁺ 25C

(1S,4R)-bicyclo[2.2.1]heptan-2-yl ((S)-2-((2,4-dioxooxazolidin-3-yl)methyl)-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 563.2 (M + H₂O)⁺ 25D

(S)-tert-butyl (2-((2,4-dioxooxazolidin-3-yl)methyl)-4-((1-methyl-1H-pyrazol-4- yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 508 (M + H)⁺ 25E

(S)-neopentyl (2-((2,4-dioxooxazolidin-3-yl)methyl)-4-((1-methyl-1H-pyrazol-4- yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 522.1 (M + H)⁺ 25F

(tetrahydro-2H-pyran-2-yl)methyl ((S)-2-((2,4-dioxooxazolidin-3-yl)methyl)-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 550.3 (M + H)⁺ 25G

(2S)-bicyclo[2.2.1]heptan-2-yl ((S)-4-((3-cyanophenyl)sulfonyl)-2-((2,4- dioxooxazolidin-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 567.1 (M + H)⁺ 25H

(2S)-bicyclo[2.2.1]heptan-2-yl ((S)-2-((2,4-dioxooxazolidin-3-yl)methyl)-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 546.1 (M + H)⁺

Example 26—Synthesis of[(S)-4-(3-cyano-benzenesulfonyl)-2-dimethylaminomethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamicacid tert-butyl ester (26)

To a solution of toluene-4-sulfonic acid(R)-6-tert-butoxycarbonylamino-4-(3-cyano-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-2-ylmethylester (1.9 g, 3.2 mmol) in tetrahydrofuran (10 mL) was addeddimethylamine (2 M in THF, 25 mL, 50 mmol) and the mixture was heated ina bomb at 100° C. overnight. The mixture was cooled and concentrated toafford[(S)-4-(3-cyano-benzenesulfonyl)-2-dimethylaminomethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamicacid tert-butyl ester. LCMS (ESI): calculated for C₂₃H₂₉ClN₄O₅S (M+H)⁺:473, Found 473.

Example 27—Synthesis of[(S)-4-(3-cyano-benzenesulfonyl)-2-dimethylaminomethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamicacid 2,2-dimethyl-propyl ester (27)

The title compound was prepared according to the procedures describedbelow.

Part I—Synthesis of3-((S)-6-amino-2-dimethylaminomethyl-2,3-dihydro-benzo[1,4]oxazine-4-sulfonyl)-benzonitrile

To a solution of[(S)-4-(3-cyano-benzenesulfonyl)-2-dimethylaminomethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamicacid tert-butyl ester (3 mmol) in p-dioxane (5 mL) was addedhydrochloric acid (4M in p-dioxane, 30 mL, 120 mmol). The mixture wasstirred at room temperature for two hours. Additional 4M HCl inp-dioxane (10 mL) was added and the mixture allowed to stir for anadditional two hours at room temperature. The mixture was quenched withsaturated sodium bicarbonate, extracted into dichloromethane, thenconcentrated and purified by HPLC to obtain3-((S)-6-amino-2-dimethylaminomethyl-2,3-dihydro-benzo[1,4]oxazine-4-sulfonyl)-benzonitrile.LCMS (ESI): calculated for C₁₈H₂₁N₄O₃S (M+H)⁺: 373, Found: 373.

Part II—Synthesis of[(S)-4-(3-cyano-benzenesulfonyl)-2-dimethylaminomethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamicacid 2,2-dimethyl-propyl ester

To a solution of3-((S)-6-amino-2-dimethylaminomethyl-2,3-dihydro-benzo[1,4]oxazine-4-sulfonyl)-benzonitrile(15 mg, 0.04 mmol) in pyridine (0.4 mL) was added neo-pentylchloroformate (6.3 mg, 0.05 mmol) in dichloromethane (0.5 mL). Themixture was stirred at room temperature overnight. The reaction wasquenched with a small amount of water and concentrated under vacuum. Theresulting residue was diluted with DMSO and purified via HPLC to obtain[(S)-4-(3-cyano-benzenesulfonyl)-2-dimethylaminomethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamicacid 2,2-dimethyl-propyl ester. LCMS (ESI): calculated for C₂₅H₂₇N₄O₈S(M+H)⁺: 543, Found: 543.

Example 28—Preparation of Additional Carbamates

The compounds in Table 9 below were prepared based on the methodsdescribed in Examples 26 and 27 and elsewhere in the detaileddescription, and can be achieved by one of skill in the art in light ofthe present disclosure.

TABLE 9 Ex. Observed No. Structure Name m/z 28A

(1S,4R)-bicyclo[2.2.1]heptan-2-yl ((S)-4-((3-cyanophenyl)sulfonyl)-2-((dimethylamino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 511.6 (M + H)⁺ 28B

(1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl ((S)-4-((3-cyanophenyl)sulfonyl)-2-((dimethylamino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 511.3 (M + H)⁺ 28C

(S)-neopentyl (2-((dimethylamino)methyl)-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 466.3 (M + H)⁺ 28D

bicyclo[2.2.1]heptan-2-yl ((S)-2-((dimethylamino)methyl)-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 490.3 (M + H)⁺ 28E

(2S)-bicyclo[2.2.1]heptan-2-yl ((S)-2-((dimethylamino)methyl)-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 490.3 (M + H)⁺ 28F

(S)-tetrahydro-2H-pyran-4-yl (4-((3- cyanophenyl)sulfonyl)-2-((dimethylamino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 499.3 (M + H)⁺

Example 29—Synthesis of (S)-methyl2-(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate(29)

The title compound was prepared according to the procedures describedbelow.

Part I—Synthesis of methyl2-(6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate

To a stirred mixture of 2-amino-4-nitrophenol (5 g, 32.4 mmol), sodiumbicarbonate (3.27 g, 38.9 mmol), and methanol (100 mL) was added asolution of methyl 4-bromocrotonate (3.82 mL, 32.4 mmol) in methanol (50mL) dropwise during a 30 minute period. The reaction mixture was stirredan additional 18 hours at room temperature. The reaction mixture wasconcentrated under reduced pressure and partitioned between ethylacetate and water. The organic layer was dried (MgSO₄) and concentrated.The residual oil was dissolved in ethanol (100 mL) and potassiumcarbonate (1.614 g, 11.68 mmol) was added. The reaction was stirred for2.5 hours at room temperature and concentrated. The residue waspartitioned between dichloromethane and water. The organic layer wasextracted with 1 N HCl. The aqueous solution was neutralized with 1NNaOH and extracted with ethyl acetate. This organic layer was dried(Na₂SO₄) and concentrated to afford the title compound. LRMS ESIcalculated for C₁₁H₁₃N₂O₅ (M+H)⁺: 253, Found: 253.

Part II—Synthesis of (R)- and (S)-methyl2-(6-((tert-butoxycarbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate

To a stirred solution of methyl2-(6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate (6.09 g,24.15 mmol) and methanol (48 mL) purged with nitrogen was added 10% Pd/C(7.71 g, 7.24 mmol) followed by di-tert-butyl dicarbonate (6.73 mL, 29.0mmol). The atmosphere above the reaction was purged and replaced with anatmosphere of hydrogen and was stirred at room temperature for 24 h. Thecrude mixture was filtered through CELITE, rinsing with methanol. Thecombined filtrates were concentrated. The residue was purified via MPLCeluting with a gradient of 0-100% ethyl acetate in hexanes. The racemicproduct was submitted for chiral SFC separation (SFC Column: ChiralTechnology AZ-H 2.1×25 cm, 5 uM; MP: 30%/70% Ethanol/CO₂ (no othermodifiers); Flow rate: 70 mL/Min, 6 min run time; WL: 220 nm; Injectionsof 0.30 ml were performed on the Berger Multigram II SFC). Mixture ofEnantiomers LRMS ESI calculated for C₁₆H₂₃N₂O₅ (M+H)⁺: 323, Found: 323;(R)-Enantiomer: LRMS ESI calculated for C₁₆H₂₃N₂O₅ (M+H)⁺: 323, Found:323; (S)-Enantiomer: LRMS ESI calculated for C₁₆H₂₃N₂O₅ (M+H)⁺: 323,Found: 323.

Part III—Synthesis of (S)-methyl2-(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate

A stirred solution of (S)-methyl2-(6-((tert-butoxycarbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate(20 mg, 0.062 mmol), 3-(trifluoromethyl)benzene-1-sulfonyl chloride(12.88 μL, 0.081 mmol) in THF (310 μL) and pyridine (310 μL) was heatedto 60° C. overnight. The mixture was cooled and partitioned betweenethyl acetate and saturated NaHCO₃. The organic layer was washed withbrine, dried (MgSO₄), and concentrated. The residue was dissolved inDMSO (1 mL), filtered, and purified by reverse phase chromatography.LRMS ESI calculated for C₁₉H₁₈F₃N₂O₇S (M+H-tBu)⁺: 475, Found: 475. ¹HNMR: (300 MHz, CDCl₃): δ 9.29 (1H, s), 8.08 (2H, m), 8.01 (2H, m), 7.84(1H, t, J=6.98 Hz), 7.03 (1H, m), 6.68 (1H, d, J=9.07 Hz), 4.44 (1H, m),3.78 (1H, m), 3.60 (3H, s), 3.37 (1H, m), 2.80 (1H, m), 2.61 (1H, m),2.48 (9H, m).

Example 30—Preparation of Additional Carbamates of (S)-methyl(benzoxazin-2-yl)acetates

The compounds in Table 10 were prepared based on the experimentalprocedures described in Example 29, and can be achieved by one of skillin the art in light of the present disclosure.

TABLE 10 Ex. Observed No. Structure Name m/z 30A

(S)-methyl 2-(6-((tert- butoxycarbonyl)amino)-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)acetate533 (M + NH₄)⁺ 30B

(S)-methyl 2-(6-((tert- butoxycarbonyl)amino)-4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate 566 (M + NH₄)⁺ 30C

(S)-methyl 2-(6-((tert- butoxycarbonyl)amino)-4-((4-fluoro-3-methoxyphenyl)sulfonyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-2-yl)acetate528 (M + NH₄)⁺ 30D

(R)-methyl 2-(6-((tert- butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate 475.1 (M-tBu + H)⁺ 30E

(S)-methyl 2-(4-((4-fluoro-3- (trifluoromethyl)phenyl)sulfonyl)-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)acetate624.7 (M + Na)⁺

Example 31—Synthesis of[(S)-6-tert-butoxycarbonylamino-4-(1-difluoromethyl-3-methyl-1H-pyrazole-4-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl]-aceticacid (31)

To a stirred solution of[(S)-6-tert-butoxycarbonylamino-4-(1-difluoromethyl-3-methyl-1H-pyrazole-4-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl]-aceticacid methyl ester (1.5 g, 2.9 mmol) in 1,2-dichloroethane was addedtrimethyltin hydroxide (2.61 g, 14.5 mmol). The mixture was heated at90° C. for 4 hours. The reaction mixture was concentrated, and theresidue was dissolved in ethyl acetate. The organic layer was washedwith 0.1N HCl and brine, dried and concentrated. The residue waspurified by flash column chromatography to afford the title compound.LRMS (ESI) calculated for C₂₀H₂₅F₂N₄O₇S (M+H)⁺: 503, Found: 503.5.

Example 32—Preparation of Additional Carbamates of(S)-(benzoxazin-2-yl)acetates

The compounds in Table 11 below were prepared based on the experimentalprocedures described in Example 31 and elsewhere in the detaileddescription, and can be achieved by one of skill in the art in light ofthe present disclosure.

TABLE 11 Ex. Observed No. Structure Name m/z 32A

(S)-2-(6-((tert-butoxycarbonyl)amino)-4-((4-fluoro-3-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2- yl)acetic acid 514 (M + NH₄)⁺ 32B

(S)-2-(6-((tert-butoxycarbonyl)amino)-4- ((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetic acid 552 (M + NH₄)⁺ 32C

(S)-2-(6-((tert-butoxycarbonyl)amino)-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2- yl)acetic acid 518 (M + NH₄)⁺ 32D

(S)-2-(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2- yl)acetic acid 461.0 (M + H-tBu)⁺32E

(S)-2-(6-((tert-butoxycarbonyl)amino)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetic acid 411.1 (M-tBu + H)⁺ 32F

(S)-2-(4-((4-fluorophenyl)sulfonyl)-6-(((neopentyloxy)carbonyl)amino)-3,4- dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetic acid 481.1 (M + H)⁺ 32G

(S)-2-(6-((tert-butoxycarbonyl)amino)-4-((3-chlorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetic acid 427.0 (M + H-tBu)⁺ 32H

(S)-2-(4-((4-fluoro-3- (trifluoromethyl)phenyl)sulfonyl)-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H- benzo[b][1,4]oxazin-2-yl)aceticacid 610.8 (M + Na)⁺

Example 33—Synthesis of(R)-6-((tert-butoxycarbonyl)amino)-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylicAcid (33)

A mixture of (R)-tert-butyl(4-((3-chloro-4-fluorophenyl)sulfonyl)-2-(hydroxymethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(500 mg, 1.057 mmol), N-methylmorpholine N-oxide (1.24 g, 10.57 mmol),tetrapropylammonium perruthenate (37.2 mg, 0.106 mmol) and acetonitrile(4.2 mL) was stirred at room temperature for fifteen minutes. Themixture was partitioned between dichloromethane and washed with pH 3buffer. The layers were separated, and the aqueous phase was extractedwith dichloromethane. The combined organic phases were dried (MgSO₄) andconcentrated. The residue was purified by reverse phase HPLC using asolvent system of MeCN/water modified with 0.1% TFA. Theproduct-containing fractions were diluted with ethyl acetate and washedwith pH 3 buffer and saturated aqueous sodium chloride. The organicphase was dried (MgSO₄) and concentrated to give(R)-6-((tert-butoxycarbonyl)amino)-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylicacid as a white foam. MS ESI calculated for C₂₀H₂₄ClFN₃O₇S (M+NH₄)⁺:504, Found: 504. ¹H NMR (600 MHz, DMSO-d6) δ 9.22 (s, 1H), 8.09 (d,J=8.0 Hz, 1H), 8.03 (s, 1H), 8.02 (s, 1H), 7.99 (s, 1H), 7.79 (t, J=7.9Hz, 1H), 6.98 (d, J=8.8 Hz, 1H), 6.64 (d, J=8.9 Hz, 1H), 4.48 (dd,J=14.0, 2.3 Hz, 1H), 3.72 (d, J=8.2 Hz, 1H), 3.25 (dd, J=14.1, 9.7 Hz,1H), 2.39 (dd, J=15.9, 5.6 Hz, 1H), 2.32 (dd, J=16.0, 7.7 Hz, 1H), 1.44(s, 9H).

Example 34—Preparation of Additional Carbamates of(R)-6-((tert-butoxycarbonyl)amino)-4-((substituted aryl orheteroaryl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylicAcids

The compounds in Table 12 below were prepared based on the experimentalprocedures described in Example 33 and elsewhere in the detaileddescription, and can be achieved by one of skill in the art in light ofthe present disclosure.

TABLE 12 Ex. Observed No. Structure Name m/z 34A

(R)-6-((tert-butoxycarbonyl)amino)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazine-2-carboxylicacid 470 (M + NH₄)⁺ 34B

(R)-6-((tert-butoxycarbonyl)amino)-4-((4-fluoro-3-methoxyphenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazine-2-carboxylic acid 500.0 (M + NH₄)⁺ 34C

(R)-4-((4-fluoro-3- (trifluoromethyl)phenyl)sulfonyl)-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H- benzo[b][1,4]oxazine-2-carboxylicacid 592.0 (M + NH₄)⁺ 34D

(R)-6-((tert-butoxycarbonyl)amino)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4- yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylic acid 511.0 (M + Na)⁺ 34E

(R)-6-((tert-butoxycarbonyl)amino)-4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2- carboxylic acid 542.9 (M + Na)⁺

Example 35—Synthesis of[(S)-2-(2-azetidin-1-yl-2-oxo-ethyl)-4-(1-difluoromethyl-3-methyl-1H-pyrazole-4-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamicacid tert-butyl ester (35)

To a stirred solution of[(S)-6-tert-butoxycarbonylamino-4-(1-difluoromethyl-3-methyl-1H-pyrazole-4-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl]-aceticacid (0.9 g, 1.8 mmol), azetidine hydrochloride salt (0.21 g, 2.34 mmol)and triethyl amine (1.5 mL, 10.8 mmol) in dichloromethane (92 mL) wasadded (benzotriazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate (1.03 g, 2.34 mmol). The mixture was heated at 40°C. for an hour, then diluted with ethyl acetate and washed with 1N NaOH,brine, 0.1N HCl and water. The organic layer was then dried andconcentrated. The residue was purified by silica gel chromatography toprovide[(S)-2-(2-azetidin-1-yl-2-oxo-ethyl)-4-(1-difluoromethyl-3-methyl-1H-pyrazole-4-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamicacid tert-butyl ester. LC/MC (ESI) m/z 542.5.

Example 36—Synthesis of[(S)-2-(2-azetidin-1-yl-2-oxo-ethyl)-4-(1-difluoromethyl-3-methyl-1H-pyrazole-4-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamicacid 1,2,2-trimethyl-propyl ester (36)

The title compound was prepared according to the procedures describedbelow.

Part I—Synthesis of2-[(S)-6-amino-4-(1-difluoromethyl-3-methyl-1H-pyrazole-4-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl]-1-azetidin-1-yl-ethanone,hydrochloride Salt

[(S)-2-(2-Azetidin-1-yl-2-oxo-ethyl)-4-(1-difluoromethyl-3-methyl-1H-pyrazole-4-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamicacid tert-butyl ester was treated with 4N HCl-dioxane (5 mL) and themixture was stirred at room temperature for one hour, then concentrated.The residual white solid was washed with ethyl acetate and dried toprovide the title compound. LC/MC (ESI) m/z 442.4.

Part II—Synthesis of[(S)-2-(2-azetidin-1-yl-2-oxo-ethyl)-4-(1-difluoromethyl-3-methyl-1H-pyrazole-4-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamicacid 1,2,2-trimethyl-propyl ester

A mixture of2-[(S)-6-amino-4-(1-difluoromethyl-3-methyl-1H-pyrazole-4-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl]-1-azetidin-1-yl-ethanone,hydrochloride salt (44 mg, 0.1 mmol) and triethyl amine in anhydrousdichloromethane (0.5 mL) was added to a stirred solution of triphosgene(6 mg, 0.03 mmol) in dichloromethane (0.1 mL) at 0° C. The resultingsolution was allowed to stir at room temperature for fifteen minutes andthen 3,3-dimethyl-butan-2-ol (15 mg, 0.15 mmol) was added, and theresulting mixture was stirred continuously for an hour. The organicphase was concentrated and the residue was purified by HPLC to afford[(S)-2-(2-azetidin-1-yl-2-oxo-ethyl)-4-(1-difluoromethyl-3-methyl-1H-pyrazole-4-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamicacid 1,2,2-trimethyl-propyl ester.

Example 37—Preparation of Additional Amides from(S)-(benzoxazin-2-yl)acetates

The compounds in Table 13 below were prepared based on the experimentalprocedures described in Examples 35 and 36 and elsewhere in the detaileddescription, and can be achieved by one of skill in the art in light ofthe present disclosure.

TABLE 13 Ex. Observed No. Structure Name m/z 37A

(S)-tert-butyl (2-(2- amino-2-oxoethyl)-4- ((4-fluorophenyl)sulfonyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-6- yl)carbamate 483 (M + H₂O)⁺ 37B

(S)-tert-butyl (2-(2- amino-2-oxoethyl)-4- ((3-(trifluoromethyl)phenyl)sulfonyl)- 3,4-dihydro-2H-benzo [b][1,4]oxazin-6- yl)carbamate460.2 (M + H-tBu)⁺ 37C

(S)-tert-butyl (4-((4- fluorophenyl) sulfonyl)-2-(2-(methylamino)-2-oxoethyl)- 3,4-dihydro- 2H-benzo[b][1,4]oxazin-6-yl)carbamate 478 (M + H)⁺ 37D

(S)-tert-butyl (2-(2- (methylamino)-2- oxoethyl)-4-((3-(trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 552 (M + Na)⁺ 37E

(S)-tert-butyl (2-(2- (dimethylamino)-2- oxoethyl)-4-((3-(trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 544 (M + H)⁺ 37F

tert-butyl (2-(2- (dimethylamino)-2- oxoethyl)-4-((4-fluorophenyl)sulfonyl)- 3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 492 (M − H)⁻ 37G

(R)-tert-butyl (4-((3-chloro-4- fluorophenyl) sulfonyl)-2-(2-(methylamino)-2-oxoethyl)- 3,4-dihydro- 2H-benzo[b][1,4]oxazin-6-yl)carbamate 514 (M + H)⁺ 37H

(S)-tert-butyl (4-((3-chloro-4- fluorophenyl) sulfonyl)-2-(2-(methylamino)-2-oxoethyl)- 3,4-dihydro- 2H-benzo[b][1,4]oxazin-6-yl)carbamate 514 (M + H)⁺ 37i

1,1,1-trifluoro-2- methylpropan-2-yl (4- ((3-chloro-4-fluorophenyl)sulfonyl)-2-(2- (methylamino)-2- oxoethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 568 (M + H)⁺ 37J

(R)-tert-butyl (2-(2- (oxazolidin-3-yl)-2- oxoethyl)-4-((3-(trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 516 (M-tBu + H)⁺ 37K

(S)-tert-butyl (2-(2- ((cyclobutylmethyl) amino)-2-oxoethyl)-4-((3-(trifluoromethyl) phenyl)sulfonyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 528 (M-tBu + H)⁺ 37L

(S)-tert-butyl (2- (2-oxo-2-((3,3,3- trifluoropropyl)amino)ethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4-dihydro-2H-benzo[b][1,4] oxazin-6- yl)carbamate 556 (M-tBu + H)⁺ 37M

(S)-tert-butyl (2-(2- (isobutylamino)-2- oxoethyl)-4-((3-(trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 516 (M-tBu + H)⁺ 37N

(S)-tert-butyl (2-(2- (((1H-pyrazol-4- yl)methyl)amino)-2-oxoethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 596 (M + H)⁺ 37o

(S)-tert-butyl (2-(2- (((1-methyl-1H- pyrazol-4-yl)methyl)amino)-2-oxoethyl)- 4-((3-(trifluoromethyl) phenyl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 610 (M + H)⁺ 37P

(S)-tert-butyl (2-(2- (((1H-pyrazol-3- yl)methyl)amino)-2-oxoethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 596 (M + H)⁺ 37Q

(S)-tert-butyl (2-(2- (((1-isopropyl-1H- pyrazol-4-yl)methyl)amino)-2-oxoethyl)- 4-((3-(trifluoromethyl) phenyl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 638 (M + H)⁺ 37R

(S)-tert-butyl (2-(2- oxo-2-((pyrazolo[1,5- a]pyridin-3-ylmethyl)amino)ethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 646 (M + H)⁺ 37S

(S)-tert-butyl (2- (2-(((1-ethyl-1H- pyrazol-3-yl)methyl)amino)-2-oxoethyl)- 4-((3-(trifluoromethyl) phenyl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 624 (M + H)⁺ 37T

(S)-tert-butyl (2-(2- (1-methylpyrrolo[3,4- c]pyrazol-5(1H,4H,6H)-yl)-2-oxoethyl)- 4-((3-(trifluoromethyl) phenyl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 622 (M + H)⁺ 37U

(S)-tert-butyl (2-(2- (((1-methyl-1H- pyrazol-3-yl)methyl)amino)-2-oxoethyl)- 4-((3-(trifluoromethyl) phenyl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 610 (M + H)⁺ 37V

(S)-tert-butyl (2- (2-(((1-ethyl-1H- pyrazol-4-yl)methyl)amino)-2-oxoethyl)- 4-((3-(trifluoromethyl) phenyl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 624 (M + H)⁺ 37W

(S)-tert-butyl (2-(2- (((1-ethyl-5-methyl- 1H-pyrazol-4-yl)methyl)amino)-2- oxoethyl)-4-((3- (trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 638 (M +H)⁺ 37X

(S)-tert-butyl (2-(2- (((1,5-dimethyl-1H- pyrazol-4-yl)methyl)amino)-2-oxoethyl)- 4-((3-(trifluoromethyl) phenyl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 624 (M + H)⁺ 37Y

(S)-tert-butyl (2-(2- (((1-benzyl-1H- pyrazol-4-yl)methyl)amino)-2-oxoethyl)- 4-((3-(trifluoromethyl) phenyl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 686 (M + H)⁺ 37Z

(S)-3-(2-(6-((tert- butoxycarbonyl) amino)-4-((3- (trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H- benzo[b][1,4]oxazin-2-yl)acetamido)propanoic acid 37AA

(S)-methyl 3-(2-(6-((tert- butoxycarbonyl) amino)-4-((3-(trifluoromethyl) phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-2- yl)acetamido) propanoate 546 (M-tBu + H)⁺ 37AB

(S)-tert-butyl (2-(2-oxo-2-((4- (trifluoromethyl)benzyl) amino)ethyl)-4-((3-(trifluoromethyl) phenyl)sulfonyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 618 (M-tBu + H)⁺ 37AC

(S)-tert-butyl (2-(2- (benzylamino)-2- oxoethyl)-4-((3-(trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 550 (M-tBu + H)⁺ 37AD

(S)-tert-butyl (2-(2- ((cyclopropylmethyl) amino)-2- oxoethyl)-4-((3-(trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 514 (M-tBu + H)⁺ 37AE

(S)-tert-butyl (2-(2-oxo-2- (propylamino) ethyl)-4-((3-(trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 502 (M-tBu + H)⁺ 37AF

(S)-tert-butyl (2-(2-(ethylamino)-2- oxoethyl)-4-((3-(trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 488 (M-tBu + H)⁺ 37AG

(S)-tert-butyl (2-(2- (oxazolidin-3-yl)-2- oxoethyl)-4-((3-(trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 516 (M-tBu + H)⁺ 37AH

(S)-neopentyl (2-(2- (methylamino)-2- oxoethyl)-4-((3-(trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 544 (M-tBu + H)⁺ 37Ai

(S)-tert-butyl (2-(2- (((2H-tetrazol-5- yl)methyl)amino)-2-oxoethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 542 (M-tBu + H)⁺ 37AJ

(S)-tert-butyl (2-(2-((2- hydroxyethyl)amino)- 2-oxoethyl)-4-((3-(trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 560 (M + H)⁺ 37AK

(S)-tert-butyl (2-(2- (tert-butylamino)-2- oxoethyl)-4-((3-(trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 516 (M-tBu + H)⁺ 37AL

tert-butyl ((2S)-2-(2- (2-methylazetidin-1- yl)-2-oxoethyl)-4-((3-(trifluoromethyl) phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 570 (M + H)⁺ 37AM

(S)-tert-butyl (2-(2- (3-cyanoazetidin-1- yl)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 581 (M + H)⁺ 37AN

(S)-tert-butyl (2-(2- (3-methoxyazetidin- 1-yl)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 586 (M + H)⁺ 37Ao

(S)-tert-butyl (2-(2- (azetidin-1-yl)-2- oxoethyl)-4-((3-(trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 556 (M + H)⁺ 37AP

(S)-tert-butyl (2-(2- (azetidin-1-yl)-2- oxoethyl)-4-((4-fluorophenyl)sulfonyl)- 3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 506.1 (M + H)⁺ 39AQ

(S)-tert-butyl (2-(2- (3-methylazetidin-1- yl)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 570 (M + H)⁺ 37AR

(S)-neopentyl (2-(2- (azetidin-1-yl)-2- oxoethyl)-4-((1-(difluoromethyl)-3- methyl-1H-pyrazol- 4-yl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 556.3 (M + H)⁺

Example 38—Preparation of amides from(R)-6-((substituted-alkoxycarbonyl)amino)-4-((substituted aryl orheteroaryl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylicAcids

The compounds in Table 14 below were prepared based on the experimentalprocedures described in Examples 33, 34 and 36 and elsewhere in thedetailed description, and can be achieved by one of skill in the art inlight of the present disclosure.

TABLE 14 Ex. Observed No. Structure Name m/z 38A

(R)-tert-butyl (2-carbamoyl-4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 537.0 (M + NH₄)⁺ 38B

(R)-1,1,1-trifluoro-2-methylpropan-2-yl (2- carbamoyl-4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 595.9 (M + Na)⁺ 38C

(R)-tert-butyl (2-carbamoyl-4-((4-fluoro-3-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 499.0 (M + NH₄)⁺ 38D

(R)-methyl 3-(6-((tert- butoxycarbonyl)amino)-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazine-2-carboxamido)propanoate 573 (M + H)⁺ 38E

(R)-tert-butyl (2-carbamoyl-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4- yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 505.0 (M + Na)⁺ 38F

(R)-tert-butyl (4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-2- (dimethylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 538.2 (M + Na)⁺ 38G

(R)-3-(6-((tert-butoxycarbonyl)amino)-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2- carboxamido)propanoic acid 575 (M +NH₄)⁺

Example 39—Synthesis of tert-butyl(2-(2-cyanopropan-2-yl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(39)

Step 1—Preparation ofN-(3-cyano-3-methyl-2-oxobutyl)-4-fluoro-N-(2-fluoro-5-nitrophenyl)benzenesulfonamide

To a stirred solution of4-fluoro-N-(2-fluoro-5-nitrophenyl)benzenesulfonamide (2 g, 6.36 mmol)in DMF (25 mL) was added NaH (0.382 g, 9.55 mmol) in one portion at 0°C. After one hour, a solution of 4-bromo-2,2-dimethyl-3-oxobutanenitrile(2.419 g, 12.73 mmol) in DMF (5 mL) was added dropwise. The mixture wasstirred at 0° C. for an additional two hours. The mixture was dilutedwith water (200 mL) and extracted with three times with ethyl acetate.The combined organic layers were washed with brine, dried (Na₂SO₄) andevaporated to dryness. The residue was cooled and triturated withpetroleum ether:ethyl acetate (1:1, 20 mL). The solid was filtered,washed twice with cold EtOAc (5 mL each) and dried to afford the titlecompound. LCMS (ESI): calculated for C₁₈H₁₅F₂N₃O₅S (M+H)⁺: 424, found:424.

Step 2—Preparation ofN-(3-cyano-2-hydroxy-3-methylbutyl)-4-fluoro-N-(2-fluoro-5-nitrophenyl)benzenesulfonamide

To a stirred solution ofN-(3-cyano-3-methyl-2-oxobutyl)-4-fluoro-N-(2-fluoro-5-nitrophenyl)benzenesulfonamide(100 mg, 0.236 mmol) in EtOH (5 mL) was added sodium borohydride (89 mg,2.362 mmol) in one portion at room temperature. The mixture was stirredat room temperature for two hours. The mixture was diluted with water(100 mL) and extracted three times with ethyl acetate. The combinedorganic layers were washed with brine, dried (Na₂SO₄) and concentrated.The residue was purified by prep-TLC eluting with petroleum ether:ethylacetate (2:1) to afford the title compound as a yellow oil. LCMS (ESI):calculated for C₁₈H₁₇F₂N₃O₅S (M+H)⁺: 426, found: 426.

Step 3—Preparation of2-(4-((4-fluorophenyl)sulfonyl)-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-methylpropanenitrile

To a stirred solution ofN-(3-cyano-2-hydroxy-3-methylbutyl)-4-fluoro-N-(2-fluoro-5-nitrophenyl)benzenesulfonamide(1.88 g, 4.42 mmol) in DMF (5 mL) was added K₂CO₃ (1.83 g, 13.26 mmol)in one portion at room temperature. The mixture was heated at 80° C. for1 h. The mixture was diluted with water (150 mL) and extracted threetimes with ethyl acetate. The combined organic layers were washed withbrine, dried (Na₂SO₄) and concentrated. The residue was purified byprep-TLC eluting with petroleum ether:ethyl acetate (2:1) to afford thetitle compound as a yellow oil. LCMS (ESI): calculated for C₁₈H₁₆FN₃O₅S(M+H)⁺: 406, found: 406.

Step 4—Preparation of tert-butyl(2-(2-cyanopropan-2-yl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of2-(4-((4-fluorophenyl)sulfonyl)-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-methylpropanenitrile(100 mg, 0.247 mmol) in ethyl acetate (10 mL) was added di-tert-butyldicarbonate (0.086 mL, 0.370 mmol) and 10% Pd/C (105 mg, 0.987 mmol) inone portion at room temperature under nitrogen. The atmosphere waspurged and exchanged with one atmosphere of hydrogen, and stirred at 30°C. for four hours. The mixture was filtered through CELITE, and thefiltrate was concentrated. The residue was purified by prep-HPLC andlyophilized under reduced pressure to afford the title compound as awhite solid. LCMS (ESI): calculated for C₂₃H₂₆FN₃O₅S (M+H)⁺: 476, found:476. ¹H-NMR (400 MHz, CDCl₃) δ 7.60-7.77 (m, 3H), 7.24 (s, 1H), 7.16 (t,J=8.42 Hz, 2H), 6.82 (d, J=8.62 Hz, 1H), 4.44 (d, J=14.10 Hz, 1H), 3.23(dd, J=13.90, 10.76 Hz, 1H), 3.07 (d, J=9.00 Hz, 1H), 1.52 (s, 9H), 1.38(s, 3H), 1.35 (s, 3H).

Example 40—Synthesis of (R and S)2-(4-((4-fluorophenyl)sulfonyl)-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-methylpropanoicAcid (40)

Step 1—Preparation of tert-butyl(4-((4-fluorophenyl)sulfonyl)-2-(2-methyl-1-oxopropan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a stirred solution of tert-butyl(2-(2-cyanopropan-2-yl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(1.4 g, 2.94 mmol) in anhydrous toluene (25 mL) at −78° C. was addeddropwise diisopropylaluminum hydride (8.83 mL, 8.83 mmol). The mixturewas stirred at −78° C. for an additional three hours. The mixture wasquenched by MeOH at −78° C. and allowed to warm up to room temperature,and then 50 mL of water and 30 mL 1M aqueous HCl solution were added(note that on larger scales, the DIBAL reduction should be quenched bythe addition of saturated aqueous Rochelle's salt). After being stirredat ambient temperature for 10 min, the resulting solution was extractedthree times with ethyl acetate. The combined organic layers were washedwith brine, dried (Na₂SO₄) and concentrated. The crude product of thetitle compound was used directly without further purification. LCMS(ESI) calculated for C₂₃H₂₇FN₂O₆S (M+H)⁺: 479, found: 479.

Step 2—Preparation of2-(6-((tert-butoxycarbonyl)amino)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-methylpropanoicAcid

To a solution of tert-butyl(4-((4-fluorophenyl)sulfonyl)-2-(2-methyl-1-oxopropan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(1.2 g, 2.508 mmol) in THF (8 mL) and water (2 mL) was added sulfamicacid (1.461 g, 15.05 mmol) and sodium chlorite (0.249 g, 2.76 mmol) inone portion at 0° C. The mixture was stirred at 0° C. for 10 min,followed by the addition of potassium dihydrogen phosphate (4.10 g, 30.1mmol). The mixture was allowed to warm to room temperature and stirredovernight. The mixture was diluted with water (80 mL) and extractedthree times with ethyl acetate. The combined organic layers were washedwith brine, dried (Na₂SO₄) and concentrated. The title compound was useddirectly without purification. LCMS (ESI) calculated for C₂₃H₂₇FN₂O₇S(M+H)⁺: 495, found: 495.

Step 3—Preparation of methyl2-(6-amino-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-methylpropanoate

To a stirred solution of2-((6-((tert-butoxycarbonyl)amino)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-methylpropanoicacid (1 g, 2.022 mmol) in methanol (10 mL) was added a 4M solution ofhydrochloric acid in methanol (30 mL, 120 mmol) at room temperature. Themixture was heated at 90° C. overnight. The mixture was concentrated,and the residue was purified by silica gel chromatography eluting withpetroleum ether:ethyl acetate (3:1) to afford the title compound as ayellow oil. LCMS (ESI) calculated for C₁₉H₂₁FN₂O₅S (M+H)⁺: 409, found:409.

Step 4—Preparation of methyl2-(4-((4-fluorophenyl)sulfonyl)-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-methylpropanoate

To a solution of methyl2-(6-amino-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-methylpropanoate(600 mg, 1.469 mmol) in DMSO (5 mL) was added1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate (424 mg,1.91 mmol) in one portion. The mixture was heated at 80° C. overnight,diluted with water (100 mL) and extracted three times with ethylacetate. The combined organic layers were washed with brine, dried(Na₂SO₄) and concentrated. The residue was purified by silica gelchromatography eluting with petroleum ether:ethyl acetate (3:1) toafford the title compound as a yellow oil. LCMS (ESI) calculated forC₂₄H₂₆F₄N₂O₇S (M+H)⁺: 563, found: 563.

Step 5—Preparation of2-(6-amino-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-methylpropanoicAcid

To a solution of methyl2-(4-((4-fluorophenyl)sulfonyl)-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-methylpropanoate(110 mg, 0.196 mmol) in THF (2 mL) and water (0.5 mL) was added lithiumhydroxide monohydrate (46.8 mg, 1.96 mmol) in one portion. The mixturewas stirred at 25° C. overnight. The mixture was diluted with water (10mL), and acidified with dilute HCl to pH=2. The mixture was extractedthree times with ethyl acetate. The combined organic layers were washedwith brine, (Na₂SO₄) and evaporated to dryness. The residue was purifiedby prep-TLC eluting with petroleum ether:ethyl acetate (1:1) to affordthe title compound as a yellow oil. LCMS (ESI) calculated forC₁₈H₁₉FN₂O₅S (M+H)⁺: 395, found: 395.

Step 6—Preparation of2-(4-((4-fluorophenyl)sulfonyl)-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-methylpropanoicAcid

To a solution of2-(6-amino-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-methylpropanoicacid (80 mg, 0.203 mmol) in DMSO (1 mL) was added1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate (54.1 mg,0.243 mmol) in one portion. The mixture was stirred at 80° C. for fourhours. The mixture was diluted with water (30 mL) and extracted threetimes with ethyl acetate. The combined organic layers were washed withbrine, dried (Na₂SO₄) and concentrated. The residue was purified byprep-HPLC to afford desired compound as a white solid. LCMS (ESI)calculated for C₂₃H₂₄F₄N₂O₇S (M+H)⁺: 549, found: 549. ¹H NMR (400 MHz,CDCl3) δ 7.78 (1H, br. s.), 7.71 (2H, dd, J=8.53, 5.02 Hz), 7.24 (1H, d,J=7.53 Hz), 7.14 (2H, t, J=8.53 Hz), 6.81 (1H, d, J=9.03 Hz), 6.63-6.77(1H, m), 4.36-4.45 (1H, m), 3.44 (1H, d, J=9.03 Hz), 3.18 (1H, dd,J=14.05, 10.54 Hz), 1.77 (6H, s), 1.25 (3H, s), 1.20 (3H, s)

Example 41—Synthesis of (R and S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-2-(2-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(41)

Step 1—Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-2-(1-hydrazinyl-2-methyl-1-oxopropan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a stirred solution at room temperature of2-(4-((4-fluorophenyl)sulfonyl)-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-methylpropanoicacid (55 mg, 0.100 mmol) in THF (2 mL) were added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (38.4 mg, 0.201 mmol),N-hydroxybenzotriazole (23 mg, 0.15 mmol) and triethylamine (0.042 mL,0.30 mmol) in one portion. After the mixture was stirred for an hour,hydrazine (9.44 μL, 0.301 mmol) solution in DMF (0.1 mL) was added tothe mixture dropwise. The reaction mixture was stirred at roomtemperature for an additional hour. The mixture was diluted with water(30 mL) and extracted three times with ethyl acetate. The combinedorganic layers were washed with brine, dried (Na₂SO₄) and evaporated todryness. The residue was purified by prep-TLC eluting with petroleumether:ethyl acetate (1:1) to afford the title compound as a colorlessoil. LCMS (ESI) calculated for C₂₃H₂₆F₄N₄O₆S (M+H)⁺: 563, found: 563.

Step 2—Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-2-(2-methyl-1-(2-(methylcarbamoyl)hydrazinyl)-1-oxopropan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a stirred solution at room temperature of1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-2-(1-hydrazinyl-2-methyl-1-oxopropan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(50 mg, 0.089 mmol) in EtOH (2 mL) was added 4-nitrophenylmethylcarbamate (52.3 mg, 0.267 mmol) in one portion. The mixture wasstirred at 100° C. overnight. The mixture was concentrated and theresidue was purified by prep-TLC eluting with dichloromethane:methanol(20:1) to afford the title compound as a colorless oil. LCMS (ESI)calculated for C₂₅H₂₉F₄N₅O₇S (M+H)⁺: 620, found: 620.

Step 3—Preparation of3-(2-(6-amino-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propan-2-yl)-4-methyl-1H-1,2,4-triazol-5(4H)-one

To a solution of 1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-2-(1-hydrazinyl-2-methyl-1-oxopropan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(15 mg, 0.027 mmol) in water (2 mL) was added K₂CO₃ (18.43 mg, 0.133mmol) in one portion at room temperature. The mixture was stirred at110° C. for two days. The mixture was diluted with water (20 mL) andextracted three times with ethyl acetate. The combined organic layerswere dried (Na₂SO₄) and concentrated. The title compound was useddirectly without purification. LCMS (ESI) calculated for C₂₀H₂₂FN₅O₄S(M+H)⁺: 448, found: 448.

Step 4—Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-2-(2-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of3-(2-(6-amino-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propan-2-yl)-4-methyl-1H-1,2,4-triazol-5(4H)-one(12 mg, 0.027 mmol) in DMSO (1 mL) was added1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate (6.55 mg,0.029 mmol) in one portion at room temperature. The mixture was stirredat 80° C. overnight. The mixture was diluted with water (20 mL) andextracted three times with ethyl acetate. The combined organic layerswere dried (Na₂SO₄) and concentrated. The residue was purified byprep-HPLC eluting with acetonitrile with 0.75% trifluoroacetic acid inwater) to afford the title compound as a white solid. LCMS (ESI)calculated for C₂₅H₂₇F₄N₅O₆S (M+H)⁺: 602, found: 602. ¹H NMR (400 MHz,CDCl₃) δ 9.12 (1H, br. s.), 7.69-7.79 (3H, m), 7.21-7.26 (1H, m), 7.17(2H, t, J=8.28 Hz), 6.79 (1H, d, J=9.03 Hz), 6.69 (1H, br. s.), 4.43(1H, d, J=13.05 Hz), 3.44 (1H, d, J=9.03 Hz), 3.32 (3H, s), 2.95 (1H,dd, J=14.56, 10.54 Hz), 1.77 (6H, s), 1.42 (3H, s), 1.40 (3H, s).

Example 42—Synthesis of (S)-tert-butyl(2-(2-oxo-2-(trifluoromethylsulfonamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(42)

A mixture of(S)-2-(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)aceticacid (500 mg, 0.968 mmol), trifluoromethanesulfonamide (173 mg, 1.162mmol), 4-N,N-dimethylaminopyridine (142 mg, 1.16 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (371 mg, 1.936 mmol), anddichloromethane (6450 μL) was stirred at room temperature for 16 hours.The mixture was concentrated, dissolved in DMSO, filtered, and purifieddirectly by reverse-phase HPLC using a gradient solvent system of10-100% MeCN/water modified with 0.1% TFA. The product-containingfractions were collected, diluted with ethyl acetate and washed with pH3 buffer. The aqueous phase was extracted with ethyl acetate, and thenthe combined organic layers were washed with saturated aqueous sodiumchloride, dried (MgSO4) and concentrated to yield (S)-tert-butyl(2-(2-oxo-2-(trifluoromethylsulfonamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamateas a white foam. MS ESI calculated for C₁₉H₁₆F₆N₃O₈S₂ (M-tBu+H)⁺: 592,Found: 592. ¹H NMR (600 MHz, DMSO-d6) δ 9.22 (s, 1H), 8.09 (d, J=8.1 Hz,1H), 8.03 (s, 1H), 8.02 (s, 1H), 7.99 (s, 1H), 7.79 (t, J=7.9 Hz, 1H),6.98 (d, J=8.7 Hz, 1H), 6.64 (d, J=8.8 Hz, 1H), 4.48 (dd, J=14.0, 2.3Hz, 1H), 3.71 (s, 1H), 3.25 (dd, J=14.1, 9.7 Hz, 1H), 2.39 (dd, J=16.0,5.5 Hz, 1H), 2.32 (dd, J=16.0, 7.7 Hz, 1H), 1.44 (s, 9H).

Example 43—Preparation of Additional Sulfonylamides of Benzoxazines

The compounds in Table 15 below were prepared based on the experimentalprocedures described in Examples 42 and elsewhere in the detaileddescription, and can be achieved by one of skill in the art in light ofthe present disclosure.

TABLE 15 Ex. Observed No. Structure Name m/z 43A

(S)-neopentyl (2-(2- (cyclopropanesulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl) phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin- 6-yl)carbamate 634 (M + H)⁺ 43B

(S)-neopentyl (4-((1- (difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-2-(2- oxo-2-(trifluoromethyl-sulfonamido)ethyl)- 3,4-dihydro-2H-benzo[b][1,4] oxazin-6-yl)carbamate670.2 (M + Na)⁺ 43C

(5)-tert-butyl (2-(2-oxo-2- (thiazole-2-sulfonamido)ethyl)-4-((3-(trifluoromethyl) phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4] oxazin-6-yl)carbamate 663 (M + H)⁺ 43D

(S)-tert-butyl (2-(2-oxo-2- (pyridine-4-sulfonamido)ethyl)-4-((3-(trifluoromethyl)phenyl) sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 657 (M + H)⁺ 43E

(S)-tert-buty (2-(2-(1,1- dimethylethylsulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl) phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin- 6-yl)carbamate 580 (M − tBu + H)⁺ 43F

(S)-tert-butyl (2-(2-oxo-2-(5- (trifluoromethyl)pyridine-2-sulfonamido)ethyl)-4-((3- (trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo [b][1,4]oxazin-6-yl)carbamate 725 (M +H)⁺ 43G

(S)-neopentyl (4-((4- fluorophenyl)sulfonyl)-2-(2-oxo-2-(trifluoromethyl- sulfonamido)ethyl)-3,4-dihydro-2H-benzo[b][1,4] oxazin-6-yl)carbamate 43H

(S)-tert-butyl (2-(2-oxo-2- (pyridine-2-sulfonamido)ethyl)-4-((3-(trifluoromethyl (phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4] oxazin-6-yl)carbamate 657 (M + H)⁺ 43i

(S)-tert-butyl (2-(2-oxo-2- (pyridine-3-sulfonamido)ethyl)-4-((3-(trifluoromethyl) phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4] oxazin-6-yl)carbamate 657 (M + H)⁺ 43J

(S)-tert-butyl (2-(2-oxo-2-(4- (trifluoromethyl)pyridine-2-sulfonamido)ethyl)-4-((3- (trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 725 (M +H)⁺ 43K

(S)-tert-butyl (2-(2-oxo-2- (1H-pyrazole-4- sulfonamido)ethyl)-4-((3-(trifluoromethyl)phenyl) sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 646 (M + H)⁺ 43L

(S)-tert-butyl (2-(2-(4- methylpyridine-2- sulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl) phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 671 (M + H)⁺ 43M

(S)-tert-butyl (2-(2-(2- fluoro-5-methylphenyl-sulfonamido)-2-oxoethyl)-4- ((3-(trifluoromethyl(phenyl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 688 (M +H)⁺ 43N

(S)-tert-butyl (2-(2-(2- fluorophenylsulfonamido)- 2-oxoethyl)-4-((3-(trifluoromethyl)phenyl) sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 674 (M + H)⁺ 43o

(S)-tert-butyl (2-(2-oxo-2-(2- (trifluoromethyl)phenyl-sulfonamido)ethyl)- 4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo [b][1,4]oxazin-6-yl)carbamate 724 (M +H)⁺ 43P

(S)-tert-butyl (2-(2-oxo-2-(3- (trifluoromethyl)phenyl-sulfonamido)ethyl)- 4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-6- yl)carbamate 724(M + H)⁺ 43Q

(S)-tert-butyl (2-(2- (3-fluorophenyl- sulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl) phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 674 (M + H)⁺ 43R

(S)-tert-butyl (2-(2- (cyclopropane- sulfonamido)-2- oxoethyl)-4-((3-(trifluoromethyl)phenyl) sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 564 (M − tBu + H)⁺ 43S

(S)-tert-butyl (2-(2-(4- methylphenyl- sulfonamido)-2-oxoethyl)-4-((3-(trifluoro- methyl)phenyl)sulfonyl)- 3,4-dihydro-2H-benzo[b][1,4]oxazin- 6-yl)carbamate 614 (M − tBu + H)⁺ 43T

(S)-tert-butyl (2-(2-(1- methylethylsulfonamido)- 2-oxoethyl)-4-((3-(trifluoromethyl) phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 639 (M + NH₄)⁺ 43U

(S)-tert-butyl (2-(2- (ethylsulfonamido)-2- oxoethyl)-4-((3-(trifluoromethyl)phenyl) sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 625 (M + NH₄)⁺ 43V

(S)-tert-butyl (2-(2- (methylsulfonamido)-2- oxoethyl)-4-((3-(trifluoromethyl)phenyl) sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 611 (M + NH₄)⁺ 43W

(S-neopentyl (2-(2- (cyclopropane- sulfonamido)-2- oxoethyl)-4-((1-(difluoromethyl)-3- methyl-1H-pyrazol-4- yl)sulfonyl)-3,4-dihydro-2H-benzo [b][1,4]oxazin-6-yl) carbamate 620 (M + H)⁺ 43X

(S)-tert-butyl (2-(2- (cyclopentane- sulfonamido)- 2-oxoethyl)-4-((3-(trifluoromethyl)phenyl) sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 648 (M + H)⁺ 43Y

(S)-tert-butyl (2-(2-(2- methylphenyl- sulfonamido)- 2-oxoethyl)-4-((3-(trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 670 (M + H)⁺ 43Z

(S)-tert-butyl (2-(2-(4- fluorophenyl- sulfonamido)- 2-oxoethyl)-4-((3-(trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 674 (M + H)⁺ 43AA

(S)-tert-butyl (2-(2-(2,5- dimethylphenyl- sulfonamido)-2-oxoethyl)-4-((3- (trifluoromethyl)phenyl) sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 684 (M + H)⁺ 43AB

(S)-tert-butyl (2-(2-oxo- 2-(4-propylphenyl- sulfonamido)ethyl)-4-((3-(trifluoromethyl)phenyl) sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 698 (M + H)⁺ 43AC

(S)-tert-butyl (2-(2-(6- methylpyridine-2- sulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl) phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 671 (M + H)⁺ 43AD

(S)-neopentyl (2-(2- (cyclopropane- sulfonamido)- 2-oxoethyl)-4-((4-fluorophenyl)sulfonyl)- 3,4-dihydro-2H-benzo [b][1,4]oxazin-6-yl)carbamate 584.0 (M + H)⁺

Example 44—Synthesis of(S)-(2-(2-(methoxyamino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamicAcid (44)

A mixture of(S)-2-(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)aceticacid (100 mg, 0.194 mmol), O-methylhydroxylamine hydrochloride (19.4 mg,0.232 mmol), (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate) (103 mg, 0.271 mmol), DMF (1290 μL), andN,N′-diisopropylethylamine (101 μL, 0.581 mmol) was stirred at roomtemperature for sixteen hours. The reaction was filtered, and purifieddirectly by mass-directed reverse phase HPLC using a mobile phase ofMeCN/water modified with 0.1% TFA to afford(S)-(2-(2-(methoxyamino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamicacid as a white solid. MS ESI calculated for C₁₉H₁₉F₃N₃O₇S (M+H)⁺: 490,Found: 490. ¹H NMR (600 MHz, DMSO-d6) δ 11.09 (s, 1H), 9.25 (s, 1H),8.10-7.94 (m, 4H), 7.82 (t, J=8.0 Hz, 1H), 7.00 (d, J=8.8 Hz, 1H), 6.66(d, J=8.9 Hz, 1H), 4.39 (dd, J=14.0, 2.2 Hz, 1H), 3.82 (s, 1H), 3.55 (s,3H), 3.37 (dd, J=14.0, 9.4 Hz, 1H), 2.35 (dd, J=14.9, 5.6 Hz, 1H), 2.22(dd, J=15.0, 7.2 Hz, 1H), 1.44 (s, 9H).

Example 45—Preparation of Additional Hydroxamates of Benzoxazines

The compounds in Table 16 below were prepared based on the experimentalprocedures described in Example 44 and elsewhere in the detaileddescription, and can be achieved by one of skill in the art in light ofthe present disclosure.

TABLE 16 Ex. Observed No. Structure Name m/z 45A

(S)-tert-butyl (2-(2-oxo-2- ((2-(trifluoromethyl)phenoxy)amino)ethyl)(trifluoromethyl) phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl) carbamate 676 (M + H)⁺ 45B

(S)-tert-butyl (2-(2-oxo-2- ((pyridin-3-ylmethoxy)amino)ethyl)-4-((3-(trifluoromethyl) phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 623 (M + H)⁺ 45C

(S)-tert-butyl (2-(2-oxo-2- (((4-(trifluoromethyl)benzyl)oxy)amino)ethyl)-4- ((3-(trifluoromethyl)phenyl) sulfonyl)-3,4-dihydro-2H-benzo[b] [1,4]oxazin-6- yl)carbamate 690 (M + H)⁺ 45D

(S)-tert-butyl (2-(2-oxo-2- (((3-(trifluoromethyl)benzyl)oxy)amino)ethyl)-4- ((3-(trifluoromethyl) phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4] oxazin-6-yl)carbamate 690 (M + H)⁺ 45E

(S)-tert-butyl (2-(2-((4- fluorophenoxy)amino)-2- oxoethyl)-4-((3-(trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 626 (M + H)⁺ 45F

(S)-tert-butyl (2-(2- ((cyclopentyloxy)amino)- 2-oxoethyl)-4-((3-(trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 600 (M + H)⁺ 45G

(S)-tert-butyl (2-(2- (ethoxyamino)-2- oxoethyl)-4-((3-(trifluoromethyl)phenyl) sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 560 (M + H)⁺ 45H

(S)-tert-butyl (2-(2- ((benzyloxy)amino)-2- oxoethyl)-4-((3-(trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 622 (M + H)⁺ 45i

(S)-tert-butyl (2-(2-(((4- methylbenzyl)oxy)amino)- 2-oxoethyl)-4-((3-(trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 636 (M + H)⁺ 45J

(S)-tert-butyl (2-(2- (isopropoxyamino)-2- oxoethyl)-4-((3-(trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 574 (M + H)⁺ 45K

(S)-tert-butyl (2-(2-oxo-2- (propoxyamino)ethyl)-4-((3-(trifluoromethyl)phenyl) sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 574 (M + H)⁺

Example 46—Synthesis of (R)-tert-butyl(4-((4-fluorophenyl)sulfonyl)-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(46)

The title compound was prepared according to the procedures describedbelow.

Part I—Synthesis of (R)-tert-butyl(4-((4-fluorophenyl)sulfonyl)-2-(hydrazinecarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of(R)-6-((tert-butoxycarbonyl)amino)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylicacid (500 mg, 1.105 mmol) in dichloromethane (20 mL) at room temperaturewas added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (318 mg, 1.66mmol) and N-hydroxybenzotriazole (254 mg, 1.658 mmol) followed byhydrazine hydrate (0.347 mL, 11.1 mmol) and the mixture was stirred atroom temperature for five hours. The reaction mixture was diluted withethyl acetate, washed with saturated aqueous sodium chloride, dried(Na₂SO₄) and concentrated. The (R)-tert-butyl(4-((4-fluorophenyl)sulfonyl)-2-(hydrazinecarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamatewas obtained as a brownish solid and used in the next step withoutfurther purification. MS ESI calculated for C₂₀H₂₃N₄O₆S (M+H)⁺: 467,Found: 411 (M-tBu).

Part II—Synthesis of (R)-tert-butyl(4-((4-fluorophenyl)sulfonyl)-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (R)-tert-butyl(4-((4-fluorophenyl)sulfonyl)-2-(hydrazinecarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(100 mg, 0.214 mmol) in acetonitrile (3 mL) at room temperature wasadded carbonyl diimidazole (52.1 mg, 0.322 mmol) followed bytriethylamine (0.045 mL, 0.322 mmol). The mixture was stirred at roomtemperature for 4 hours, then concentrated. The residue was dissolved inDMSO, filtered and purified by reverse phase HPLC using a mobile phaseof MeCN/water modified with 0.1% TFA to yield (R)-tert-butyl(4-((4-fluorophenyl)sulfonyl)-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamateas a white solid. MS ESI calculated for C₂₁H₂₁FN₄O₇S (M+H)⁺: 493, Found:493. ¹H NMR (500 MHz, DMSO-d6) δ 12.59 (s, 1H), 9.35 (s, 1H), 7.97-7.80(m, 3H), 7.44 (t, J=8.8 Hz, 2H), 7.15 (d, J=10.3 Hz, 1H), 6.83 (d, J=8.9Hz, 1H), 4.80 (d, J=5.1 Hz, 1H), 4.39 (dd, J=14.3, 2.9 Hz, 1H), 3.89(dd, J=14.3, 8.0 Hz, 1H), 1.49 (s, 9H).

Example 47—Preparation of Additional2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl) Substituted Benzoxazines

The compounds in Table 17 below were prepared based on the experimentalprocedures described in Example 46 and elsewhere in the detaileddescription, and can be achieved by one of skill in the art in light ofthe present disclosure.

TABLE 17 Ex. Observed No. Structure Name m/z 47A

(R)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((4-fluorophenyl)sulfonyl)-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 547.0 (M + H)⁺ 47B

(R)-tert-butyl (4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 473.1 (M − tBu + H)⁺ 47C

(R)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 604.9(M + Na)⁺ 47D

(R)-tert-butyl (4-((3-chloro-4- fluorophenyl)sulfonyl)-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 544 (M + NH₄)⁺ 47E

(R)-tert-butyl (4-((4-fluoro-3- (trifluoromethyl)phenyl)sulfonyl)-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 578.0 (M + NH₄)⁺ 47F

(S)-tert-butyl (4-((4- fluorophenyl)sulfonyl)-2-((4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4] oxazin-6-yl)carbamate 543 (M + Na)⁺47G

(S)-tert-butyl (4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-2-((4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol- 2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 579 (M + Na)⁺ 47H

(S)-tert-butyl (2-((4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 593 (M + Na)⁺

Example 48—Synthesis of (R)-tert-butyl(4-((4-fluorophenyl)sulfonyl)-2-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(48)

The title compound was prepared according to the procedures describedbelow.

Part I—Synthesis of (R)-tert-butyl(4-((4-fluorophenyl)sulfonyl)-2-(hydrazinecarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of(R)-6-((tert-butoxycarbonyl)amino)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylicacid (400 mg, 0.884 mmol) in dichloromethane (20 mL) at room temperaturewas added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (254 mg, 1.326mmol) and N-hydroxybenzotriazole (203 mg, 1.326 mmol) followed byhydrazine hydrate (0.28 mL, 8.84 mmol). The mixture was stirred at roomtemperature for sixteen hours. The reaction mixture was diluted withethyl acetate, washed with saturated aqueous sodium chloride, dried(Na₂SO₄) and concentrated. The residue was purified by silica gelchromatography eluting with a gradient of ethyl acetate/hexane (0˜100%)to give (R)-tert-butyl(4-((4-fluorophenyl)sulfonyl)-2-(hydrazinecarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamateas a white solid. MS ESI calculated for C₂₀H₂₃N₄O₆S (M+H)⁺: 467, Found:411 (M-tBu).

Part II—Synthesis of (R)-tert-butyl(4-((4-fluorophenyl)sulfonyl)-2-(2-(methylcarbamoyl)hydrazinecarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To (R)-tert-butyl(4-((4-fluorophenyl)sulfonyl)-2-(hydrazinecarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(200 mg, 0.429 mmol) in THF (2 mL) at room temperature was added methylisocyanate (0.032 mL, 0.51 mmol) and the mixture was stirred at roomtemperature for three hours. The reaction mixture was diluted with ethylacetate, washed with saturated aqueous NaHCO₃, and saturated aqueoussodium chloride, dried (Na₂SO₄) and concentrated to afford(R)-tert-butyl(4-((4-fluorophenyl)sulfonyl)-2-(2-(methylcarbamoyl)hydrazinecarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamatewhich was used in the next step without further purification.

Part III—Synthesis of (R)-tert-butyl(4-((4-fluorophenyl)sulfonyl)-2-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To (R)-tert-butyl(4-((4-fluorophenyl)sulfonyl)-2-(2-(methylcarbamoyl)hydrazinecarbonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(200 mg, 0.382 mmol) at room temperature was added 2M NaOH (3 mL, 6.00mmol) and the mixture was stirred at 100° C. for sixteen hours. Thereaction mixture was allowed to cool to room temperature, acidified with1N HCl (6 mL) and concentrated. The residue was redissolved in DMSO,filtered and purified by reverse phase HPLC using a solvent system ofMeCN/water modified with 0.1% trifluoroacetic acid to give(R)-tert-butyl(4-((4-fluorophenyl)sulfonyl)-2-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate.MS ESI calculated for C₂₂H₂₄FN₅O₆S (M+H)⁺: 506, Found: 506 and 450(M-tBu). ¹H NMR (500 MHz, DMSO-d6) δ 11.88 (s, 1H), 9.34 (s, 1H),7.92-7.82 (m, 3H), 7.43-7.40 (m, 2H), 7.14 (s, 1H), 6.81 (d, J=8.8 Hz,1H), 4.77 (d, J=6.9 Hz, 1H), 4.50 (d, J=11.7 Hz, 1H), 3.83 (dd, J=13.9,9.2 Hz, 1H), 1.45 (s, 9H).

Example 49—Synthesis of tert-butyl(2-(cyanomethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(49)

The title compound was prepared according to the procedures describedbelow.

Part I—Synthesis of (R)-tert-butyl(2-(iodomethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a stirred solution of(R)-(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl4-methylbenzenesulfonate (7.7 g, 12 mmol) in acetone (100 mL) was addedsodium iodide (7.0 g, 47 mmol). The mixture was heated at 60° C. andstirred overnight. Solvent was evaporated, brine (50 mL) was added, andthe mixture was extracted three times with ethyl acetate (50 mL each).The combined organic phases were dried (Na₂SO₄) and concentrated. Theresidue was purified by column chromatography on silica gel eluting withethyl acetate/hexanes 1:4 to afford (R)-tert-butyl(2-(iodomethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamateas a white solid. LCMS (ESI) calculated for C₂₁H₂₂F₃IN₂NaO₅S (M+Na)⁺:621.0, Found: 620.9.

Part II—Synthesis of tert-butyl(2-(cyanomethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a stirred solution of (R)-tert-butyl(2-(iodomethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(3.0 g, 5 mmol) in DMF (30 mL) was added sodium cyanide (490 mg, 10mmol) at room temperature. The reaction was stirred overnight. Themixture was diluted with brine (50 mL) and extracted three times withethyl acetate (50 mL each). The organic layers were combined, dried(Na₂SO₄) and concentrated. The residue was purified by Prep-HPLC to givea brown solid as a racemate. LCMS (ESI) calculated for C₂₂H₂₂F₃N₃NaO₅S(M+Na)⁺: 520.1, Found: 520.0.

Example 50—Synthesis of tert-butyl(2-(2-hydroxypropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(50)

The title compound was prepared according to the procedures describedbelow.

Part I—Synthesis of tert-butyl(2-(2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a stirred solution of tert-butyl(2-(cyanomethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(1.0 g, 2.0 mmol) in anhydrous toluene (30 mL) was added a 1M solutionof diisobutylaluminum hydride (5 mL, 5 mmol) in toluene at −78° C. Themixture was stirred at −78° C. for one hour and then warmed to roomtemperature. The reaction was stirred for another hour, and quenchedwith brine (50 mL). The mixture was extracted three times with ethylacetate (50 mL each). The organic phases were combined, dried (Na₂SO₄),filtered, and concentrated to afford tert-butyl(2-(2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamateas a yellow solid. LCMS (ESI) calculated for C₂₂H₂₃F₃N₂NaO₆S (M+Na)⁺:523.1, Found: 523.0.

Part II—Synthesis of tert-butyl(2-(2-hydroxypropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a stirred solution of tert-butyl(2-(2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(150 mg, 0.3 mmol) in anhydrous THF (10 mL) was added a 3M solution ofmethyl magnesium bromide (1.0 mL, 3.0 mmol) in THF dropwise at 0° C. Themixture was stirred at 0° C. for an hour, warmed to room temperature andstirred for another hour, then quenched with saturated aqueous ammoniumchloride (5 mL). Brine (10 mL) was added and extracted three times withethyl acetate (20 mL each). The organic layers were combined, dried(Na₂SO₄) and concentrated. The residue was purified by Prep-HPLC toafford the title compound as a white solid. LCMS (ESI): calculated forC₂₃H₃₁F₃N₃O₆S (M+NH₄)⁺: 534.2, Found: 534.0.

Example 51—Synthesis of (S)-tert-butyl(2-(2-amino-2-methylpropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (51)

Cerium chloride (4.6 g, 18.0 mmol) was dried under vacuum at 140° C. for2 hours before it was cooled to room temperature. Anhydrous THF (140 mL)was added and the suspension was stirred at room temperature for twohours. Then the suspension was cooled to −78° C., and 3M methyl lithium(6.0 mL, 18.0 mmol) in ether was added dropwise. The mixture was stirredat −78° C. for thirty minutes. A solution of tert-butyl(2-(cyanomethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(1.5 g, 3.0 mmol) in THF (15 mL) was added dropwise and the mixture wasstirred for another thirty minutes at −78° C. The resulting mixture waswarmed to room temperature and stirred for 1.5 hours. Ammonium hydroxide(25-28% in water, 3 mL) was added and the resulting solution was stirredfor ten minutes. Brine (40 mL) was added and extracted with ethylacetate (30 mL×3). The organic layers were combined, dried (Na₂SO₄),concentrated and the residue purified by prep-HPLC (46-76%acetonitrile+0.75%0 trifluoroacetic acid in water) and SFC-HPLC to givetwo isomers. SFC separation condition: Column: Chiralpak AS-H 250×4.6 mmI.D., Sum Mobile phase: ethanol (0.05% DEA) in CO2 from 5% to 40% Flowrate: 2.35 mL/min Wavelength: 220 nm. (S)-tert-butyl(2-(2-amino-2-methylpropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate RT:5.294 min. LCMS (ESI): calculated for C₂₄H₃₁F₃N₃O₅S (M+H)⁺: 530, Found:530; and (R)-tert-butyl(2-(2-amino-2-methylpropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate RT:4.789 min. LCMS (ESI): calculated for C₂₄H₃₁F₃N₃O₅S (M+H)⁺: 530, Found:530.

Example 52—Synthesis of (S)-tert-butyl(2-(2-acetamido-2-methylpropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(52)

To a stirred solution of (S)-tert-butyl(2-(2-amino-2-methylpropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(180 mg, 0.34 mmol) and triethyl amine (0.1 mL, 0.7 mmol) indichloromethane (5 mL) was added acetic anhydride (71 mg, 0.7 mmol) atroom temperature. The mixture was stirred at room temperature overnight.The solvent was evaporated, brine (20 mL) was added and the mixture wasextracted with ethyl acetate (50 mL×3). The organic layers werecombined, dried (Na₂SO₄) and concentrated. The residue was purified byprep-HPLC (45-75% acetonitrile+0.75‰ trifluoroacetic acid in water) togive (S)-tert-butyl(2-(2-acetamido-2-methylpropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamateas a white solid. ¹H NMR (400 MHz, CD₃OD) δ 8.08 (br s, 1H), 8.04˜7.95(m, 2H), 7.83˜7.76 (m, 1H), 7.61 (s, 1H), 7.04 (dd, J=2.0, 8.6 Hz, 1H),6.70 (d, J=8.6 Hz, 1H), 4.28 (dd, J=2.4, 14.4 Hz, 1H), 3.63 (br s, 1H),3.28˜3.21 (m, 1H), 2.17 (dd, J=2.8, 14.8 Hz, 1H), 1.91 (s, 3H),1.90˜1.84 (m, 1H), 1.55 (s, 9H), 1.29 (d, J=6.6 Hz, 6H). LCMS (ESI):calculated for C₂₆H₃₃F₃N₃O₆S (M+H)⁺: 572, Found: 572.

Example 53—Preparation of Additional Amides of Benzoxazines

The compounds in Table 18 below were prepared based on the experimentalprocedures described in Examples 49, 50, 51 and 52 and elsewhere in thedetailed description, and can be achieved by one of skill in the art inlight of the present disclosure.

TABLE 18 Ex. Observed No. Structure Name m/z 53A

(S)-tert-butyl (2-(2-propionamidoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 558 (M + H)⁺ 53B

tert-butyl ((2S)-2-(2-(2- hydroxypropanamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 574 (M + H)⁺ 53C

(S)-tert-butyl (2-(2-(oxetane-3- carboxamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 586 (M + H)⁺ 53D

(S)-tert-butyl (2-(2-isobutyramidoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 572 (M + H)⁺ 53E

(S)-tert-butyl (2-(2-acetamidoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 566 (M + Na)⁺ 53F

(S)-tert-butyl (2-(2- (cyclopropanecarboxamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 570 (M + H)⁺ 53G

(S)-tert-butyl (4-((4- fluorophenyl)sulfonyl)-2-(2-propionamidoethyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate508 (M + H)⁺ 53H

(S)-tert-butyl (2-(2-acetamidoethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 494 (M + H)⁺ 53i

tert-butyl ((2S)-4-((4- fluorophenyl)sulfonyl)-2-(2-(2-hydroxypropanamido)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 524 (M + H)⁺ 53J

(S)-tert-butyl (2-(2- (cyclopropanecarboxamido)ethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 520 (M + H)⁺ 53K

(S)-neopentyl (4-((4- fluorophenyl)sulfonyl)-2-(2-propionamidoethyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate522 (M + H)⁺ 53L

(S)-neopentyl (2-(2-acetamidoethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 508 (M + H)⁺ 53M

(S)-neopentyl (2-(2- (cyclopropanecarboxamido)ethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 533 (M + H)⁺ 53N

(S)-1,1,l-trifluoro-2-methylpropan-2-yl(2-(2-amino-2-methylpropyl)-4-((3- chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 568 (M + H)⁺ 53o

(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-amino-2-methylpropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 584 (M + H)⁺ 53P

(R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-(2-oxopyrrolidin-1-yl)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 624 (M + H)⁺ 53Q

(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-(2-oxopyrrolidin-1-yl)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 624 (M + H)⁺

Example 54—Synthesis of (S)-tert-butyl(2-(2-acetamido-2-methylpropyl)-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (54)

The title compound was prepared according to the procedures describedbelow.

Part I—Synthesis of (S)-benzyl6-((tert-butoxycarbonyl)amino)-2-(2-methoxy-2-oxoethyl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate

To a solution of (S)-methyl2-(6-((tert-butoxycarbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate(0.5 g, 1.6 mmol) and sodium bicarbonate (0.52 g, 6.2 mmol) in dry THF(5 mL) was added benzyl chloroformate (0.53 g, 6.2 mmol) at 0° C. Themixture was stirred at reflux for an hour, poured into ice-water (10mL), and extracted with ethyl acetate (10 mL×3). The combined organiclayers were washed with brine (5 mL), dried (Na₂SO₄) and concentrated toafford compound (S)-benzyl6-((tert-butoxycarbonyl)amino)-2-(2-methoxy-2-oxoethyl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylateas a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.89 (br s, 1H), 7.31˜7.48(m, 5H), 7.07 (br s, 1H), 6.80 (d, J=8.8 Hz, 1H), 6.37 (br s, 1H), 5.26(s, 2H), 4.52˜4.64 (m, 1H), 4.21 (dd, J=2.4, 13.2 Hz, 1H), 3.70 (s, 3H),3.49 (dd, J=7.6, 13.2 Hz, 1H), 2.66˜2.77 (m, 1H), 2.54˜2.64 (m, 1H),1.50 (s, 9H). LCMS (ESI): calculated for C₂₄H₂₉N₂O₇ (M+H)⁺: 457, Found:457.

Part II—Synthesis of (S)-benzyl6-((tert-butoxycarbonyl)amino)-2-(2-hydroxy-2-methylpropyl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate

To a solution of (S)-benzyl6-((tert-butoxycarbonyl)amino)-2-(2-methoxy-2-oxoethyl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate(0.4 g, 0.88 mmol) in dry THF (5 mL) at 0° C. was added dropwise 3Mmethyl magnesium bromide (2.9 mL, 8.7 mmol) in THF. The mixture wasstirred at room temperature for five hours. The resulting mixture wasquenched with saturated aqueous ammonium chloride (10 mL) and extractedwith ethyl acetate (10 mL×3). The combined organic layers were dried(Na₂SO₄) and concentrated to afford (S)-benzyl6-((tert-butoxycarbonyl)amino)-2-(2-hydroxy-2-methylpropyl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylateas a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.91 (br s, 1H), 7.30˜7.47(m, 5H), 7.07 (br s, 1H), 6.79 (d, J=8.8 Hz, 1H), 6.35 (br s, 1H), 5.26(s, 2H), 4.36˜4.49 (m, 1H), 4.18 (dd, J=2.0, 13.6 Hz, 1H), 3.37 (dd,J=8.0, 13.2 Hz, 1H), 2.40 (br s, 1H), 1.80˜1.91 (m, 1H), 1.67 (dd,J=3.2, 14.8 Hz, 1H), 1.50 (s, 9H), 1.31 (d, J=9.6 Hz, 6H). LCMS (ESI):calculated for C₂₅H₃₃N₂O₆ (M+H)⁺: 457, Found: 457.

Part III—Synthesis of (S)-benzyl2-(2-acetamido-2-methylpropyl)-6-amino-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate

To a solution of compound (S)-benzyl6-((tert-butoxycarbonyl)amino)-2-(2-hydroxy-2-methylpropyl)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate(0.05 g, 0.11 mmol) in acetonitrile (5 mL) was added dropwiseconcentrated sulfuric acid (107 mg, 1.1 mmol) at 0° C. The mixture wasstirred at room temperature for 5 hours. The resulting mixture waspoured into ice-water (3 mL) and extracted with ethyl acetate (10 mL×3).The combined organic layers were washed with brine (5 mL), dried(Na₂SO₄) and concentrated to afford compound (S)-benzyl2-(2-acetamido-2-methylpropyl)-6-amino-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate.¹H NMR (400 MHz, CDCl₃) δ 7.33-7.43 (m, 5H), 6.63 (d, J=8.4 Hz, 1H),6.37 (dd, J=2.8, 8.8 Hz, 1H), 5.95 (br s, 1H), 5.24 (s, 2H), 4.21 (t,J=8.8 Hz, 1H), 4.05 (dd, J=2.0, 13.2 Hz, 1H), 3.40 (dd, J=8.4, 13.2 Hz,1H), 1.97˜2.04 (m, 2H), 1.79-1.90 (m, 3H), 1.34 (s, 6H). LCMS (ESI):calculated for C₂₂H₂₈N₃O₄ (M+H)⁺: 398, Found: 398.

Part IV—Synthesis of (S)-benzyl2-(2-acetamido-2-methylpropyl)-6-((tert-butoxycarbonyl)amino)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate

To a solution of (S)-benzyl2-(2-acetamido-2-methylpropyl)-6-amino-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate(1.2 g, 3 mmol) and sodium bicarbonate (0.5 g, 6 mmol) in methanol (5mL) was added di-tert-butyl dicarbonate (0.94 g, 4.5 mmol) at 0° C. Themixture was stirred at room temperature for two hours. The resultingmixture was poured into ice-water (10 mL) and extracted with ethylacetate (10 mL×3). The combined organic layers were washed with brine (5mL), dried (Na₂SO₄) and concentrated to afford (S)-benzyl2-(2-acetamido-2-methylpropyl)-6-((tert-butoxycarbonyl)amino)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate.¹H NMR (400 MHz, CDCl₃) δ 7.95 (br s, 1H), 7.37-7.44 (m, 5H), 7.11 (brs, 1H), 6.75 (d, J=8.8 Hz, 1H), 6.48 (br s, 1H), 6.14 (br s, 1H),5.24˜5.30 (m, 2H), 4.27 (t, J=8.4 Hz, 1H), 4.05˜4.09 (d, J=13.6 Hz, 1H),3.41˜3.46 (dd, J=8.4, 13.6 Hz, 1H), 1.88˜2.06 (m, 5H), 1.52 (s, 9H),1.43 (s, 6H). LCMS (ESI): calculated for C₂₇H₃₆N₃O₆ (M+H)⁺: 498, Found:498.

Part V—Synthesis of (S)-tert-butyl(2-(2-acetamido-2-methylpropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution (S)-benzyl2-(2-acetamido-2-methylpropyl)-6-((tert-butoxycarbonyl)amino)-2H-benzo[b][1,4]oxazine-4(3H)-carboxylate(1 g, 2 mmol) in ethyl acetate (10 mL) was added 10% Pd/C (200 mg, 10%wt) under nitrogen. The mixture was stirred at room temperature underhydrogen at 1 atmosphere for three hours. The resulting mixture wasfiltered through a CELITE pad and the filtrate was concentrated toafford (S)-tert-butyl(2-(2-acetamido-2-methylpropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamateas a white solid. ¹H NMR (400 MHz, CDCl₃) δ 6.89 (br s, 1H), 6.62 (d,J=8.4 Hz, 1H), 6.41 (d, J=8.0 Hz, 1H), 6.33 (br s, 1H), 6.15 (br s, 1H),4.19˜4.31 (m, 1H), 3.21˜3.34 (m, 1H), 3.08˜3.19 (m, 1H), 1.89˜1.95 (m,5H), 1.44 (s, 9H), 1.34 (s, 6H). LCMS (ESI): calculated for C₁₉H₃₀N₃O₄(M+H)⁺: 364, Found: 364.

Part VI—Synthesis of (S)-tert-butyl(2-(2-acetamido-2-methylpropyl)-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (S)-tert-butyl(2-(2-acetamido-2-methylpropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(0.05 g, 0.1 mmol) and pyridine (1 mL) in dry THF (2 mL) was addedsulfonyl chloride (0.06 g, 1.1 mmol) at 0° C. The mixture was stirred atreflux for an hour. The resulting mixture was poured into ice-water (10mL) and extracted with ethyl acetate (10 mL×3). The combined organiclayers were washed with brine (5 mL), dried (Na₂SO₄) and concentrated.The residue was purified by prep-HPLC (45-75% acetonitrile+0.75%0trifluoroacetic acid in water) to give (S)-tert-butyl(2-(2-acetamido-2-methylpropyl)-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamateas a white solid. ¹H NMR (400 MHz, CDCl₃) δ 7.89 (d, J=5.2 Hz, 1H), 7.74(br s, 1H), 7.61 (br s, 1H), 7.09˜7.25 (m, 2H), 6.71 (d, J=8.8 Hz, 1H),6.43 (br s, 1H), 5.58 (br s, 1H), 4.13 (d, J=13.6 Hz, 1H), 3.63˜3.80 (m,1H), 3.20 (dd, J=9.6, 14.0 Hz, 1H), 2.13 (d, J=14.0 Hz, 1H), 1.92 (s,3H), 1.79 (dd, J=8.4, 14.8 Hz, 1H), 1.52 (s, 9H), 1.34 (d, J=6.8 Hz,6H). LCMS (ESI): calculated for C₂₅H₃₂ClFN₃O₄S (M+H)⁺: 556, Found: 556.

Example 55—Preparation of Additional Amides of Benzoxazines

The compounds in Table 19 below were prepared based on the experimentalprocedures described in Example 54 and elsewhere in the detaileddescription, and can be achieved by one of skill in the art in light ofthe present disclosure.

TABLE 19 Ex. Observed No. Structure Name m/z 55A

(S)-tert-butyl (2-(2-acetamido-2- methylpropyl)-4-((3,4-difluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 540 (M + H)⁺ 55B

(S)-tert-butyl (2-(2-acetamido-2-methylpropyl)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 558 (M + H)⁺ 55C

(S)-tert-butyl (2-(2-acetamido-2-methylpropyl)-4-((1-(difluoromethyl)-5-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 558 (M + H)⁺ 55D

(S)-tert-butyl (2-(2-acetamido-2-methylpropyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 522 (M + H)⁺ 55E

(R)-tert-butyl (2-(2-acetamido-2-methylpropyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 522 (M + H)⁺

Example 56—Synthesis of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-acetamido-2-methylpropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(56)

A mixture of(S)—N-(1-(6-amino-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-methylpropan-2-yl)acetamide(100 mg, 0.21 mmol), 4-nitrophenyl 1,1,1-trifluoro-2-methylpropan-2-ylcarbonate (130 mg, 0.44 mmol) and N,N′-diisopropylethylamine (0.2 mL)were stirred at 120° C. for two hours. The mixture was diluted withwater and extracted with ethyl acetate. The organic layers were washedwith 1N NaOH, brine, (Na₂SO₄) and concentrated. The residue was purifiedby prep-TLC (petroleum ether:ethyl acetate=1:1) and prep-HPLC to give(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-acetamido-2-methylpropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate. ¹HNMR (400 MHz, CDCl₃) δ 8.08 (br s, 1H), 7.92 (d, J=7.6 Hz, 1H), 7.85 (d,J=7.6 Hz, 2H), 7.60˜7.69 (m, 1H), 7.07 (dd, J=8.8, 2.2 Hz, 1H), 6.71 (d,J=9.2 Hz, 1H), 6.65 (s, 1H), 5.92 (br s, 1H), 4.13˜4.18 (m, 1H), 3.73(br s, 1H), 3.23 (dd, J=14.0, 9.6 Hz, 1H), 1.95˜2.03 (m, 4H), 1.83˜1.92(m, 1H), 1.76 (s, 6H), 1.36 (s, 3H), 1.30 (s, 3H). LCMS (ESI):calculated for C₂₆H₃₀F6N₃O₆S (M+H)⁺: 626, Found: 626.

Example 57—Preparation of Additional Amides of Benzoxazines

The compounds in Table 20 below were prepared based on the experimentalprocedures described in Example 56 and elsewhere in the detaileddescription, and can be achieved by one of skill in the art in light ofthe present disclosure.

TABLE 20 Ex. Observed No. Structure Name m/z 57A

(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-acetamido-2-methylpropyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 576 (M + H)⁺ 57B

(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-acetamido-2-methylpropyl)-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 610 (M + H)⁺ 57C

(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-acetamido-2-methylpropyl)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol- 4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 612 (M + H)⁺ 57D

(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-2-(2- methyl-2-(methylsulfonamido)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 612 (M + H)⁺ 57E

(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-acetamido-2-methylpropyl)-4- ((3,4-difluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 594 (M + H)⁺ 57F

(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-4-fluorophenyl)sulfonyl)- 2-(2-methyl-2-(methylsulfonamido)propyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 668 (M + Na)⁺ 57G

(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3,4-difluorophenyl)sulfonyl)-2-(2-methyl-2-(methylsulfonamido)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 630 (M + H)⁺ 57H

(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-(cyclopropanesulfonamido)-2- methylpropyl)-4-((3,4-difluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 678 (M + Na)⁺ 57i

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(2-methyl-2-(methylsulfonamido)propyl)-4-((3- (trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 684 (M + Na)⁺ 57J

(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-(cyclopropanesulfonamido)-2- methylpropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 710 (M + Na)⁺ 57K

(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-4-fluorophenyl)sulfonyl)- 2-(2-methyl-2-(methylsulfonamido)propyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 694 (M + Na)⁺ 57L

(S)-1,1,1-trifluoro-2-mrthylpropan-2-yl(2-(2-(cyclopropanrsulfonamido)-2- methylpropyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 638 (M + H)⁺ 57M

(R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-(cyclopropanesulfonamido)-2- methylpropyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 638 (M + H)⁺ 57N

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(2-methyl-2-(trifluoromethylsulfonamido)propyl)-4-((3-(trifluoromethyl(phenyl(sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 716 (M + H)⁺ 57o

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (2-(2-(2-(dimethylamino)-2-oxoacetamido)-2-methylpropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 683 (M + H)⁺ 57P

(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-acetamido-2-methylpropyl)-4-((4- fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-carbamate 644 (M + H)⁺ 57Q

(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-acetamido-2-methylpropyl)-4-((3- chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 611 (M +H)⁺ 57R

(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-acetamido-2-methylpropyl)-4-((3-methoxy-1,5-dimethyl-1H-pyrazol-4- yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 606 (M + H)⁺ 57S

(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-acetamido-2-methylpropyl)-4-((1-(difluoromethyl)-3-ethoxy-1H-pyrazol-4- yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 642 (M + H)⁺ 57T

(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-acetamido-2-methylpropyl)-4-((3-(difluoromethoxy)-1-ethyl-1H-pyrazol-4- yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 642 (M + H)⁺ 57U

2,2,2-trifluoro-1,1-dimethylethyl [(2S)-2-[2-(acetylamino)-2-methylpropyl]-4-{[l-ethyl-3-(2-hydroxyethoxy)-1H-pyrazol-4- yl]sulfonyl}-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbamate 636 (M + H)⁺

Example 58—Synthesis of tert-butyl(2-(2-hydroxyethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(58)

To a solution of(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)aceticacid (240 mg, 0.47 mmol) in anhydrous THF (10 mL) was added 1 M solutionof borane (4.5 mL, 4.65 mmol) in THF at 0° C. The mixture was stirred atroom temperature overnight and quenched with methanol (5 mL). Themixture was concentrated, diluted with water (20 mL), and extractedthree times with ethyl acetate (15 mL each). The organic layers werecombined (Na₂SO₄) and concentrated. The residue was purified by reversephase chromatography (water/MeOH=50/50) MPLC to give the title compound.LCMS (ESI) calculated for C₂₂H₂₅F₃N₂NaO₆S (M+Na)⁺: 525.1, Found: 525.1.¹H NMR (400 MHz, CD₃OD): δ 8.08 (1H, s), 8.04 (2H, d, J=8.8 Hz), 7.96(1H, d, J=7.6 Hz), 7.75 (1H, t, J=8.0 Hz), 7.03 (1H, dd, J=8.4, 2.0 Hz),6.72 (1H, d, J=8.4 Hz), 4.47 (1H, dd, J=14.4, 2.0 Hz), 3.63-3.70 (3H,m), 3.24-3.30 (1H, m), 1.74-1.78 (2H, m), 1.55 (9H, s).

Example 59—Synthesis of tert-butyl(2-((1H-imidazol-2-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(59)

Aqueous ammonium hydroxide (25% w/w, 0.15 mL) was added to solution of(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)aceticacid (145 mg, 0.29 mmol) in methanol (2 mL). Glyoxal (40% (w/w) inwater, 0.05 mL) was added dropwise to the above mixture and the reactionwas stirred at room temperature for twelve hours. The solvent wasremoved and the residue was purified by Prep-HPLC to afford the titlecompound. LCMS (ESI) calculated for C₂₄H₂₆F₃N₄O₅S (M+H)⁺: 539.2, Found:539.0. ¹H NMR (400 MHz, CD₃OD): δ 8.02-7.94 (4H, m), 7.74 (1H, t, J=7.6Hz), 7.05-7.01 (3H, m), 6.76 (1H, d, J=8.8 Hz), 4.42 (1H, d, J=14.4 Hz),3.76-3.74 (1H, m), 3.23 (1H, dd, J=14, 9.6 Hz), 3.03-2.97 (2H, m), 1.54(9H, s).

Example 60—Synthesis of tert-butyl(2-((1-methyl-1H-imidazol-2-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(60)

To a solution of tert-butyl(2-((1H-imidazol-2-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(30 mg, 0.056 mmol) in DMF (2 mL) was added potassium carbonate (12 mg,0.084 mmol) and methyl iodide (8 mg, 0.056 mmol) at 0° C. The reactionwas stirred at room temperature for twelve hours and then concentrated.The residue was purified by Prep-HPLC to afford the title compound. LCMS(ESI) calculated for C₂₅H₂₈F₃N₄O₅S (M+H)⁺: 553.2, Found: 553.2. ¹H NMR(400 MHz, CD₃OD): δ 7.93-7.89 (3H, m), 7.84 (1H, d, J=8.0 Hz), 7.63 (1H,t, J=8.0 Hz), 6.92-6.90 (2H, m), 6.80 (1H, s), 6.60 (1H, d, J=8.8 Hz),4.34 (1H, dd, J=14.4 Hz, 2.4 Hz), 3.75-3.69 (1H, m), 3.51 (3H, s),3.23-3.17 (1H, m), 2.93 (2H, d, J=6.0 Hz), 1.42 (9H, s).

Example 61—Synthesis of (S)-tert-butyl(4-((4-fluorophenyl)sulfonyl)-2-((2-oxopyrrolidin-1-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(61)

A mixture of(S)-(6-((tert-butoxycarbonyl)amino)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl4-methylbenzenesulfonate (81.6 mg, 0.138 mmol), ethyl 4-aminobutanoate(93 mg, 0.708 mmol), and NMP (1377 μL) was stirred for three days at100° C. The mixture was cooled, diluted with ethyl acetate and washedwith saturated NaHCO₃ and brine. The combined organic layers were dried(MgSO₄) and concentrated. Purification via chromatography eluting with agradient of 100% hexanes to 100% ethyl acetate afforded (S)-tert-butyl(4-((4-fluorophenyl)sulfonyl)-2-(2-oxopyrrolidin-1-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate.LRMS (ESI) calculated for C₂₀H₂₀FN₃O₆S (M-tBu+H)⁺: 450, Found: 450. ¹HNMR (500 MHz, DMSO-d6) δ 9.29 (s, 1H), 7.86 (s, 1H), 7.78 (m, 2H), 7.43(t, 2H, J=7.95 Hz), 7.14 (d, 1H, J=8.97 Hz), 6.73 (d, 1H, J=8.96 Hz),4.16 (d, 1H, J=14.5 Hz), 3.47 (m, 1H), 3.43 (m, 2H), 3.22 (m, 2H), 3.19(m, 1H), 2.22 (m, 2H), 1.92 (m, 2H), 1.46 (s, 9H).

Example 62—Synthesis of (S)-tert-butyl(2-((1H-pyrazol-1-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(62)

To a suspension of sodium hydride (6.18 mg, 0.154 mmol) in DMF (1 mL) atroom temperature was added a solution of 1H-pyrazole (9.01 mg, 0.132mmol) in DMF (1 mL) and the reaction mixture was stirred for tenminutes. A solution of(R)-(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methylmethanesulfonate (50 mg, 0.088 mmol) in DMF (2 mL) was added and themixture was heated at 120° C. for fifteen minutes. The mixture wascooled, diluted with ethyl acetate, washed with water and brine, dried(Na₂SO₄), filtered and concentrated. The residue was purified by reversephase HPLC using a solvent system of MeCN/water with 0.1%trifluoroacetic acid to yield (S)-tert-butyl(2-((1H-pyrazol-1-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamateas white solid. MS ESI calculated for C₂₄H₂₅F₃N₄O₂S (M+H)⁺: 539, Found:539. ¹H NMR (600 MHz, DMSO-d6) δ 9.27 (s, 1H), 8.10-7.88 (m, 4H), 7.79(t, J=7.9 Hz, 1H), 7.66 (d, J=2.2 Hz, 1H), 7.45 (s, 1H), 7.02 (d, J=6.9Hz, 1H), 6.68 (d, J=8.9 Hz, 1H), 6.23 (s, 1H), 4.42-4.27 (m, 3H), 3.80(s, 1H), 3.47 (s, 2H), 3.28 (dd, J=14.2, 9.7 Hz, 1H), 1.43 (s, 9H).

Example 63—Preparation of Additional Heteroatom Linked Heterocycles

The compounds in Table 21 below were prepared based on the experimentalprocedures described in Examples 61 and 62 and elsewhere in the detaileddescription, and can be achieved by one of skill in the art in light ofthe present disclosure. In cases of where two products could beobtained, both were isolated via HPLC chromatography.

TABLE 21 Ex. Observed No. Structure Name m/z 63A

(S)-tert-butyl (2-((2H-1,2,3-triazol-2-yl)methyl-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 470.1 (M − tBu)⁺ 63B

(S)-tert-butyl (2-((4H-1,2,4-triazol-4- yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 540.2 (M + H)⁺ 63C

(S)-tert-butyl (2-((1H-1,2,4-triazol-1- yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 540.2 (M + H)⁺ 63D

(S)-tert-butyl (2-((1H-1,2,3-triazol-1-yl)methyl)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 526.1 (M + H)⁺ 63E

(S)-tert-butyl (2-((1H-1,2,3-triazol-1- yl)methyl)-4-((3-(trifluoromethyl(phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 540.1 (M + H)⁺ 63F

(S)-tert-butyl (2-((2H-1,2,3-triazol-2- yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 484.0 (M − tBu)⁺ 63G

(R)-tert-butyl (2-((pyridin-2-yloxy(methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 588.0 (M + Na)⁺ 63H

(S)-tert-butyl (2-((2-oxopyridin-1(2H)- yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 566.0 (M + H)⁺

Example 64—Synthesis of (S)-tert-butyl(2-((5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(64)

The title compound was prepared according to the procedures describedbelow.

Part I—Synthesis of (S)-tert-butyl(2-(cyanomethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of(S)-2-(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)aceticacid (200 mg, 0.387 mmol), ammonium chloride (41.4 mg, 0.774 mmol) and(O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate) (221 mg, 0.581 mmol) in dichloromethane (5 mL) atroom temperature was added N,N′-diisopropylethylamine (0.20 mL, 1.16mmol) and the mixture was stirred at room temperature for sixty hours.The mixture was concentrated, and then dissolved in DMF (3 mL). To DMF(1 mL) at 0° C. was added phosphoryl trichloride (0.18 mL, 1.94 mmol)dropwise and the mixture was stirred at room temperature for thirtyminutes. The crude solution of the amide was added and the mixture wasstirred at room temperature for an additional sixteen hours. Thereaction mixture was poured into ice, and extracted with ethyl acetate.The organic phase was washed with saturated aqueous sodium chloride,dried (Na₂SO₄) filtered and concentrated. The residue was purified bysilica gel chromatography eluting with a gradient of ethylacetate/hexane (0˜25%) to afford (S)-tert-butyl(2-(cyanomethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate.MS ESI calculated for C₂₂H₂₂F₃N₃O₅S (M+H)⁺: 498, Found: 442 (M-tBu) and520 (M+Na).

Part II—Synthesis of (S)-tert-butyl(2-(2-(hydroxyamino)-2-iminoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (S)-tert-butyl(2-(cyanomethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(80 mg, 0.16 mmol) in ethanol (5 mL) was added hydroxylaminehydrochloride (22.4 mg, 0.322 mmol) followed by potassium carbonate(66.7 mg, 0.482 mmol) and the mixture was heated at 70° C. for sixteenhours. Additional hydroxamine hydrochloride (20 mg) was added and themixture was stirred at 80° C. for an additional five hours. The reactionwas cooled to room temperature, filtered and washed with methanol. Thefiltrate was concentrated to afford (S)-tert-butyl(2-(2-(hydroxyamino)-2-iminoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate,which was used without further purification.

Part III—Synthesis of (S)-tert-butyl(2-((5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To the above prepared (S)-tert-butyl(2-(2-(hydroxyamino)-2-iminoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(0.16 mmol) in acetonitrile (5 mL) was added carbonyl diimidazole (36.7mg, 0.226 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.091 mL, 0.60mmol). The mixture was stirred at room temperature for three hours. Themixture was concentrated and the residue was purified by reverse phaseHPLC using a solvent system of MeCN/water modified with 0.1%trifluoroacetic acid to yield (S)-tert-butyl(2-((5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamateas white solid. MS ESI calculated for C₂₃H₂₃F₃N₄O₇S (M+H)⁺: 557, Found:501 (M-tBu). ¹H NMR (600 MHz, DMSO-d6) δ 12.10 (s, 1H), 9.27 (s, 1H),8.19-7.94 (m, 4H), 7.82 (d, J=7.7 Hz, 1H), 6.99 (s, 1H), 6.73 (d, J=9.0Hz, 1H), 4.95 (s, 1H), 4.47 (d, J=14.0 Hz, 2H), 3.32 (m, 1H), 3.01 (d,J=11.1 Hz, 1H), 2.80 (d, J=7.8 Hz, 1H), 1.46 (s, 9H).

Example 65—Synthesis of tert-butyl(2-(2-hydroxy-2-methylpropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(65)

To a stirred solution of 3 M methyl magnesium bromide in THF (0.9 mL,2.7 mmol) in anhydrous THF (5 mL) was added a solution of methyl2-(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate(140 mg, 0.26 mmol) in THF (2 mL) dropwise at 0° C. The mixture wasstirred at 0° C. for an hour and then warmed to room temperature. Thereaction was stirred for another hour and saturated aqueous ammoniumchloride solution (2 mL) was added. The reaction mixture was dilutedwith brine (20 mL) and extracted twice with ethyl acetate. The combinedorganic layers were dried (Na₂SO₄) and concentrated. The residue waspurified by Prep-HPLC to afford the product as a white solid. LCMS (ESI)calculated for C₂₄H₂₉F₃N₂NaO₆S: (M+Na)⁺: 553.2, Found: 553.0.

Example 66—Synthesis of (S)-tert-butyl(2-((3-hydroxyazetidin-1-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(66)

To a solution of(R)-(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl4-methylbenzenesulfonate (300 mg, 0.467 mmol) in ethanol (7 mL) wasadded azetidin-3-ol hydrochloride (256 mg, 2.33 mmol) and potassiumcarbonate (645 mg, 4.67 mmol). The mixture was heated at 100° C.overnight. The reaction mixture was filtered and concentrated. Theresidue was purified by Prep-TLC (20*20 cm) (petroleum ether/ethylacetate 1/6) to afford the title compound. LCMS (ESI) calculated forC₂₄H₂₉F₃SN₃O₆ (M+H)⁺: 544.2, Found: 544.0. ¹HNMR (500 MHz, MeOD): δ7.97-8.07 (4H, m), 7.77 (1H, t, J=8.0 Hz), 7.06 (1H, dd, J=9.0, 2.5 Hz),6.74 (1H, d, J=9.0 Hz), 4.33-4.39 (2H, m), 3.68-3.71 (1H, m), 3.59-3.62(1H, m), 3.46-3.48 (1H, m), 3.28-3.31 (1H, m), 2.92-2.96 (2H, m),2.64-2.68 (2H, m), 1.55 (9H, s).

Example 67—Preparation of Additional Amines of Benzoxazines

The compounds in Table 22 below were prepared based on the experimentalprocedures described in Example 66 and elsewhere in the detaileddescription, and can be achieved by one of skill in the art in light ofthe present disclosure.

TABLE 22 Ex. Observed No. Structure Name m/z 67A

(S)-tert-butyl (2-(((3-methyloxetan-3- yl)amino)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 558 (M + H)⁺ 67B

tert-butyl ((2S)-4-((3- (trifluoromethyl)phenyl)sulfonyl)-2-(((1,1,1-trifluoropropan-2- yl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 584 (M + NH₄)⁺ 67C

1,1,1-trifluoro-2-methylpropan-2-yl ((2S)-4-((4-fluorophenyl)sulfonyl)-2-((2-methylazetidin-1-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 546.1 (M + H)⁺ 67D

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (4-((4-fluorophenyl)sulfonyl)-2-((3-hydroxyazetidin-1-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 548.1 (M + H)⁺ 67E

(S)-1,1,1-trifluoro-2-methylpropan-2-yl (2- (azetidin-1-ylmethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 532.1 (M + H)⁺

Example 68—Synthesis of (S)-tert-butyl(3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)carbamate(68)

The title compound was prepared according to the procedures describedbelow.

Part I—Synthesis of (S)-methyl6-((1-methoxy-1-oxopropan-2-yl)oxy)-5-nitronicotinate

To methyl (S)-lactate (5.8 g, 55.4 mmol) and methyl6-chloro-5-nitropyridine-3-carboxylate (10 g, 46 mmol) in anhydroustetrahydrofuran (100 mL) under nitrogen with activated molecular sievesat 0° C. was added 1,8-diazabicyclo[5.4.0]undec-7-ene (9 mL, 60 mmol).The solution quickly turned dark, was stirred at 0° C. for thirtyminutes, then was allowed to stir at ambient temperature for an hour. Asolid precipitated out of solution. The solution was diluted with ethylacetate, solids were filtered off, and then the filtrates wereconcentrated. The residue was purified by column chromatography elutingwith a gradient of 10-50% ethyl acetate in hexanes to yield the titlecompound.

Part II—Synthesis of (S)-methyl3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylate

In a three necked round bottomed flask equipped with an overhead stirrerwas added (S)-methyl6-((1-methoxy-1-oxopropan-2-yl)oxy)-5-nitronicotinate (9.09 g, 32 mmol)and acetic acid (100 mL). Powdered iron was carefully added (8.9 g, 160mmol) and the suspension was heated at 70° C. for 2 hours. The reactionwas cooled, filtered through CELITE and washed with 5% methanol intetrahydrofuran (3×50 mL). The combined filtrates were concentrated to avolume of approximately 50 mL comprising mostly acetic acid and product.Upon the addition of water (100 mL), a solid crashed out, which wasslurried and filtered off and washed with water to yield the titlecompound.

Part III—Synthesis of(S)-3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylicAcid

To (S)-methyl3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylate(3.9 g, 17.6 mmol) in tetrahydrofuran (30 mL) and methanol (10 mL) wasadded 2M sodium hydroxide and the reaction stirred at ambienttemperature overnight. The volume was concentrated to 20 mL. Thesolution was acidified with 1 M hydrogen chloride (40 mL). The resultingsolids were slurried for 20 minutes, filtered and dried to yield thetitle compound.

Part IV—Synthesis of (S)-tert-butyl(3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)carbamate

To a solution of(S)-3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylicacid (2.39 g, 11.5 mmol) in anhydrous toluene (20 mL) and anhydroustert-butanol (20 mL) with triethylamine (3.5 mL, 25 mmol) was addedactivated molecular sieves, and the resulting mixture was stirred forfifteen minutes before the addition of diphenylphosphoryl azide (3 mL,13.8 mmol). The reaction was heated to reflux under nitrogen for twohours. Upon completion, the solution was cooled, filtered over filterpaper, diluted with ethyl acetate, washed with water, brine, dried(Na₂SO₄) and concentrated. The residue was purified by columnchromatography eluting with a gradient of 20-80% ethyl acetate inhexanes. The resulting product was repurified by column chromatographyeluting with a gradient of 0-10% methanol in dichloromethane to yieldthe title compound.

Part V—Synthesis of (S)-tert-butyl(3-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)carbamate

To a solution of (S)-tert-butyl(3-methyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)carbamate(3.5 g, 12.5 mmol) in anhydrous tetrahydrofuran (40 mL) under nitrogenat 0° C. was added 1 M lithium aluminum hydride in tetrahydrofuran (38mL, 38 mmol) dropwise. The reaction was stirred at 0° C. for threehours, then at ambient temperature for an hour. The suspension wasrecooled to 0° C. before carefully quenching it with sodium sulfatedecahydrate. The suspension was slurried at ambient temperature for 1hour before filtering solids off over CELITE. The residue was purifiedby column chromatography eluting with a gradient of 0.5-5% methanol indichloromethane to yield the title compound (0.91 g, 27%).

Example 69—Synthesis of[(R)-1-((3-chloro-benzenesulfonyl)-3-hydroxymethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl]-carbamicacid tert-butyl ester (69)

To a solution((R)-3-hydroxymethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-carbamicacid tert-butyl ester (0.56 g, 2 mmol) in pyridine (5 mL) at 0° C. wasadded 3-chloro phenyl sulfonyl chloride (0.42 g, 2 mmol). The reactionmixture was stirred at room temperature for two hours. The reactionmixture was diluted with ethyl acetate, washed with brine, saturatedsodium bicarbonate and water. The organic layer was separated, dried(Na₂SO₄) and concentrated. The crude product was purified by columnchromatography on silica gel (hexanes/AcOEt 2:1 to 1:3) to afford thetitle compound as a white foam. LCMS (ESI) m/z 456.

Example 70—Synthesis of[(S)-1-(3-Chloro-benzenesulfonyl)-3-(2,4-dioxo-oxazolidin-3-ylmethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl]-carbamicacid tert-butyl ester (70)

To a solution of (91 mg, 0.2 mmol)[(R)-1-((3-chloro-benzenesulfonyl)-3-hydroxymethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl]-carbamicacid tert-butyl ester), oxazolidine-2,4-dione (20 mg, 0.20 mmol),triphenylphosphine (78.6 mg, 0.30 mmol) in THF (2 mL) was added DIAD(60.6 mg, 0.30 mmol) and the mixture was stirred for 12 hours at roomtemperature. The mixture was concentrated, and the residue was purifiedby column chromatography to afford[(S)-1-(3-Chloro-benzenesulfonyl)-3-(2,4-dioxo-oxazolidin-3-ylmethyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl]-carbamicacid tert-butyl ester. LCMS (ESI) m/z 539.1.

Example 71—Synthesis of4-[(S)-6-amino-4-((3-chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-2-ylmethyl]-1-methyl-piperazin-2-one(71)

The title compound was prepared according to the procedures describedbelow.

Part I—Synthesis of 3-chloro-benzenesulfonic acid(R)-7-tert-butoxycarbonylamino-1-(3-chloro-benzenesulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-3-ylmethyl ester

To a solution((R)-3-hydroxymethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-carbamicacid tert-butyl ester (0.56 g, 2 mmol) in pyridine (5 mL) was added3-chlorobenzenesulphonyl chloride (0.42 g, 2 mmol). The resultingmixture was stirred for 15 minutes at 0° C., and then a secondequivalent of sulfonyl chloride was added and stirring continued for anhour. The reaction mixture was diluted with ethyl acetate, washed withwater, dried (Na₂SO₄) and concentrated. The residue was purified bycolumn chromatography eluting with hexanes/ethyl acetate 2:1) to afford3-chloro-benzenesulfonic acid(R)-6-tert-butoxycarbonylamino-4-((3-chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-2-ylmethylester. LCMS (ESI) m/z 630.3.

Part II—Synthesis of4-[(S)-6-amino-4-((3-chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-2-ylmethyl]-1-methyl-piperazin-2-one

A suspension of 3-chloro-benzenesulfonic acid(R)-6-tert-butoxycarbonylamino-4-((3-chloro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-2-ylmethyl ester (63 mg, 0.1 mmol), N,N′-diisopropylethylamine (2 eq),1-methyl-piperazin-2-one hydrochloride salt (30 mg, 0.2 mmol) andpotassium iodide (cat.) in THF/NMP (0.5 mL) was heated in a sealed tubefor 12 h at 80° C. The mixture was partitioned between water and ethylacetate. The organic layer was separated, washed with brine, saturatedNaHCO₃ and concentrated. The residue was purified by columnchromatography on silica gel to provide[(S)-4-((3-chloro-benzenesulfonyl)-2-(4-methyl-3-oxo-piperazin-1-ylmethyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamicacid tert-butyl ester. LCMS (ESI) m/z 551.

Example 72—Synthesis of (S)-tert-butyl(5-((4-fluorophenyl)sulfonyl)-6-methyl-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate(72)

The title compound was prepared according to the procedures describedbelow.

Part I—Synthesis of1-benzyl-7-bromo-2-methyl-1,2,3,4-tetrahydro-1,5-naphthyridine

To a solution of 1-benzyl-7-bromo-3,4-dihydro-1,5-naphthyridin-2(1H)-one(1.42 g, 4.48 mmol) in anhydrous tetrahydrofuran (20 mL) under anitrogen atmosphere at 0° C. was added 1M methylmagnesium bromide intetrahydrofuran (17.9 mL, 17.9 mmol) slowly. The resulting red solutionwas stirred at ambient temperature for 2 hours, then the solution washeated for 2 hours to 50° C. To the cooled solution was slowly addedacetic acid (6 mL). The resulting mixture was stirred for two minutes,then was added sodium borohydride (0.42 g, 11.2 mmol). The reaction wasstirred at ambient temperature overnight. The reaction mixture wasbasified with 2M sodium hydroxide (12 mL), and extracted with ethylacetate twice. The combined extracts were washed with brine, dried withsodium sulfate, filtered, and concentrated in the presence of silica.The residue was purified by column chromatography eluting with agradient of ethyl acetate in hexanes to yield the title compound.

Part II—Synthesis of tert-butyl(5-benzyl-6-methyl-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate

1-Benzyl-7-bromo-2-methyl-1,2,3,4-tetrahydro-1,5-naphthyridine (0.56 g,1.77 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.04g, 0.09 mmol), tripotassium phosphate (1.1 g, 5.3 mmol), and tert-butylcarbamate (0.31 g, 2.6 mmol) were combined in toluene (5 mL) and water(1 mL). The reaction was degassed, then treated withtris(dibenzylideneacetone)dipalladium(0) (0.08 g, 0.09 mmol) andrefluxed overnight. The solution was cooled, partitioned between ethylacetate and brine, separated, dried (Na₂SO₄) and concentrated in thepresence of silica. The residue was purified by column chromatographyeluting with a gradient of ethyl acetate in hexane to yield the titlecompound.

Part III—Synthesis of tert-butyl(6-methyl-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate

To a degassed suspension of tert-butyl(5-benzyl-6-methyl-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate(0.26 g, 0.74 mmol) and ammonium formate (0.93 g, 14.7 mmol) under anitrogen atmosphere in methanol (5 mL) was added 10% palladium on carbon(78 mg). The suspension was refluxed for three hours. The reaction wascooled to ambient temperature, filtered through CELITE, rinsing withmethanol and concentrated. The residue was redissolved in ethyl acetate,washed with water, brine, dried with sodium sulfate, filtered andconcentrated to yield the title compound.

Part IV—Synthesis of (S)-tert-butyl(5-((4-fluorophenyl)sulfonyl)-6-methyl-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate

To a solution of tert-butyl(6-methyl-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate (0.13 g,0.49 mmol) in anhydrous pyridine (2 mL) was added4-fluorobenzenesulfonyl chloride (0.14 g, 0.74 mmol) and the reactionwas heated at 60° C. for 8 hours. The reaction was cooled, diluted withethyl acetate, washed with 10% citric acid, water, and brine. Theorganics were dried with sodium sulfate, filtered and concentrated inthe presence of silica. The residue was purified by columnchromatography eluting with a gradient of methanol in dichloromethane.The purified racemic mixture was separated by preparatory chiral HPLC toyield the title compounds. ¹H NMR (400 Hz, DMSO-d6) δ 9.59 (s, 1H), 8.34(s, 1H), 8.16 (s, 1H), 7.61 (m, 2H), 7.37 (m, 2H), 4.37 (m, 1H), 2.5 (m,1H), 2.06 (m, 1H), 1.57 (m, 1H), 1.46 (s, 9H), 1.12 (m, 3H).

Example 73—Synthesis of (S)-benzyl tert-butyl(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydro-1,5-naphthyridine-3,7-diyl)dicarbamate(73)

The title compound was prepared according to the procedures describedbelow.

Part I—Synthesis of methyl 5-amino-6-chloronicotinate

To methyl 6-chloro-5-nitro-pyridine-3-carboxylate (2.0 g, 9.2 mmol) inanhydrous methanol (30 mL) under nitrogen was added tin (II) chloride(5.3 g, 28 mmol). The resulting mixture was refluxed for eighteen hours.Then, the reaction mixture was cooled and then poured carefully into astirred slurry of CELITE in saturated sodium bicarbonate at 0° C. Theresulting suspension was stirred for twenty minutes before the mixturewas filtered through CELITE to remove the solids. The solids were washedwith ethyl acetate, and the filtrates were collected, washed with water,and washed with brine. The resulting organic solution was dried withsodium sulfate (Na₂SO₄) and concentrated to provide the title compound.

Part II—Synthesis of methyl7-((tert-butoxycarbonyl)amino)-6-oxo-5,6,7,8-tetrahydro-1,5-naphthyridine-3-carboxylate

An oven-dried flask was charged with zinc powder (2.0 g, 30 mmol) andiodine (0.12 g, 0.46 mmol), and flushed with nitrogen. Next, the flaskwas cooled in an ice bath and a solution of methyl(2S)-2-(tert-butoxycarbonylamino)-3-iodo-propanoate (5.0 g, 15 mmol) inanhydrous N,N-dimethylformamide (20 mL) was added to the flask. Theresulting reaction mixture was stirred at 0° C. for 90 minutes. Then,solid methyl 5-amino-6-chloronicotinate (3.7 g, 19.7 mmol) was addedfollowed by addition of dichlorobistriphenyl-phosphine palladium (II)(0.53 g, 0.76 mmol). Then, the reaction mixture was heated at 40° C. for18 hours. Next, the reaction mixture was filtered through CELITE,washing with ethyl acetate. The resulting organic solution wasconcentrated in vacuo to provide a residue that was redissolved inN,N-dimethylformamide (20 mL). To the resulting organic solution,potassium carbonate (2.5 g, 18 mmol) was added and the reaction mixturewas heated at 80° C. for 2 hours. The resulting solution was partitionedbetween ethyl acetate and saturated ammonium chloride. The organic layerwas separated and washed with water and brine. The resulting organicsolution was dried with sodium sulfate, filtered, and concentrated invacuo to provide a residue that was purified by column chromatographyeluting with a gradient of 20-100% ethyl acetate in hexanes to providethe title compound.

Part III—Synthesis of7-((tert-butoxycarbonyl)amino)-6-oxo-5,6,7,8-tetrahydro-1,5-naphthyridine-3-carboxylicAcid

To (R)-methyl7-((tert-butoxycarbonyl)amino)-6-oxo-5,6,7,8-tetrahydro-1,5-naphthyridine-3-carboxylate(2.63 g, 8.2 mmol) in tetrahydrofuran (20 mL) and methanol (20 mL) wasadded 2M sodium hydroxide (12 mL, 24 mmol). The reaction mixture wasstirred at ambient temperature for two hours. Then, the volume of thereaction mixture was reduced in vacuo. The resulting solution waspartitioned between ethyl acetate and 10% citric acid. The organic layerwas isolated, washed with brine, dried with sodium sulfate, filtered,and concentrated in vacuo to yield the title compound.

Part IV—Synthesis of benzyl tert-butyl(2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridine-3,7-diyl)dicarbamate

To(R)-7-((tert-butoxycarbonyl)amino)-6-oxo-5,6,7,8-tetrahydro-1,5-naphthyridine-3-carboxylicacid (2.07 g, 6.74 mmol) in anhydrous toluene (20 mL) and benzyl alcohol(2.1 mL, 20 mmol) was added activated 4 Å molecular sieves andtriethylamine (2.1 mL, 14.8 mmol). The resulting mixture was stirred atambient temperature for 10 minutes, then diphenylphosphorylazide (1.7mL, 8.1 mmol) was added. Next, the resulting suspension was refluxed for2 hours. Then, the reaction mixture was filtered hot through CELITE,washing with ethyl acetate. The resulting organic solution wasconcentrated onto silica in vacuo to provide a residue that was purifiedby column chromatography eluting with a gradient of methanol indichloromethane to provide the title compound.

Part V—Synthesis of benzyl tert-butyl(1,2,3,4-tetrahydro-1,5-naphthyridine-3,7-diyl)dicarbamate

To a solution of benzyl tert-butyl(2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridine-3,7-diyl)dicarbamate (5.35g, 13 mmol) in anhydrous tetrahydrofuran (140 mL) under nitrogen at 0°C. was added solid lithium aluminum hydride (2.5 g, 65 mmol) inportions. After complete addition of the lithium aluminum hydride, thecooling bath was removed and the reaction was stirred at ambienttemperature for 3 hours. The reaction was recooled to 0° C. beforecarefully quenching it with water (2.5 mL), 15% sodium hydroxide (2.5mL), then water (7.5 mL). The solids were filtered through CELITE andwashed with tetrahydrofuran, and then the filtrates were concentrated inthe presence of silica. The residue was purified by columnchromatography eluting with a gradient of methanol in dichloromethane toyield the title compound.

Part VI—Synthesis of (S)-benzyl tert-butyl(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydro-1,5-naphthyridine-3,7-diyl)dicarbamate

To (S)-benzyl tert-butyl(1,2,3,4-tetrahydro-1,5-naphthyridine-3,7-diyl)dicarbamate (0.28 g, 0.70mmol) in anhydrous pyridine (4 mL) was added 4-fluorobenzenesulfonylchloride (0.17 g, 0.88 mmol) and the mixture was heated at 60° C. for 4hours. The mixture was cooled, diluted with ethyl acetate, washed withcitric acid, water, brine, dried with sodium sulfate, filtered andconcentrated in the presence of silica. The residue was purified bycolumn chromatography eluting with a gradient of methanol indichloromethane to yield the title compound. LRMS (ESI) calculated forC₂₇H₃₀FN₄O₆S (M+H)⁺: 557, Found: 557.

Example 74—Preparation of Additional Sulfonamides from benzyl tert-butyl(1,2,3,4-tetrahydro-1,5-naphthyridine-3,7-diyl)dicarbamate

The compounds in Table 24 below were prepared based on the experimentalprocedures described in Example 73 and elsewhere in the detaileddescription, and can be achieved by one of skill in the art in light ofthe present disclosure.

TABLE 24 Ex. Observed No. Structure Name m/z 74A

benzyl tert-butyl (1-((3- (trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydro-1,5-naphthyridine-3,7- diyl)dicarbamate 629.17 (M + Na)⁺ 74B

benzyl tert-butyl (1-((3- cyanophenyl)sulfonyl)-1,2,3,4-tetrahydro-1,5-naphthyridine-3,7-diyl)dicarbamate 586.14 (M + Na)⁺ 74C

benzyl tert-butyl (1-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-1,2,3,4-tetrahydro-1,5-naphthyridine-3,7- diyl)dicarbamate 615.19 (M + Na)⁺

Example 75—Synthesis of (S)-benzyl(5-((4-fluorophenyl)sulfonyl)-7-(2-oxopyrrolidin-1-yl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate(75)

Part 1—Synthesis of (S)-benzyl(7-amino-5-((4-fluorophenyl)sulfonyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate

The carbamate from Example 73 was separated by chiral chromatography toafford the two isomers. Products from the first to elute are isomer A,while products from the second to elute are isomer B. To a solution of(S)-benzyl tert-butyl(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydro-1,5-naphthyridine-3,7-diyl)dicarbamate(0.34 g, 0.61 mmol) in dichloromethane (3 mL) was added trifluoroaceticacid (2 mL) and the reaction was stirred at ambient temperature for 2hours. The reaction was concentrated and dissolved in ethyl acetate,washed with saturated sodium bicarbonate, brine, dried (Na₂SO₄) andconcentrated to yield the title compound. LRMS (ESI) calculated forC₂₂H₂₂FN₄O₄S (M+H)⁺: 457, Found: 457.

Part 2—Synthesis of (S)-benzyl(5-((4-fluorophenyl)sulfonyl)-7-(2-oxopyrrolidin-1-yl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate

To a solution of (S)-benzyl(7-amino-5-((4-fluorophenyl)sulfonyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate(135 mg, 0.3 mmol) in dichloromethane (1.5 mL) and tetrahydrofuran (1.5mL) was added tetraalkylammonium carbonate resin (0.49 g, 1.5 mmol)followed by 4-chlorobutyryl chloride (99 μL, 0.89 mmol) and theresulting solution was shaken at ambient temperature for 4 hours. Theresin was filtered off and the filtrate was concentrated in the presenceof silica. The crude product was purified by column chromatographyeluting with a gradient of methanol in dichloromethane. The material wasredissolved in anhydrous tetrahydrofuran (3 mL) under a nitrogenatmosphere, cooled to −78° C., then treated with 1M potassiumtert-butoxide in tetrahydrofuran (0.59 mL, 0.59 mmol). After 20 minutesthe reaction was warmed to 0° C. After 20 minutes the reaction wasquenched by adding silica gel and concentrated. The residue was purifiedby column chromatography eluting with a gradient of methanol indichloromethane to yield the title compound. LRMS (ESI) calculated forC₂₆H₂₆FN₄O₅S (M+H)⁺: 525, Found: 525.

Example 76—Synthesis of (S)-neopentyl(5-((4-fluorophenyl)sulfonyl)-7-(2-oxopyrrolidin-1-yl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamateand (R)-neopentyl(5-((4-fluorophenyl)sulfonyl)-7-(2-oxopyrrolidin-1-yl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate(Example Nos. 76A and 76B)

The title compounds were prepared according to the procedures describedbelow.

Part I—Synthesis of(S)-1-(7-amino-1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)pyrrolidin-2-one

To a degassed suspension of (S)-benzyl(5-((4-fluorophenyl)sulfonyl)-7-(2-oxopyrrolidin-1-yl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamatefrom Example 75 (60 mg, 0.11 mmol) and ammonium formate (72 mg, 1.1mmol) in methanol (4 mL) under a nitrogen atmosphere was added 10%palladium on carbon (12 mg) and the reaction was refluxed for 2 hours.The reaction was cooled to ambient temperature, then filtered through aCELITE cartridge washing through with methanol. The solution wasconcentrated to yield the title compound, which was used without furtherpurification.

Part II—Synthesis of (S)-neopentyl(5-((4-fluorophenyl)sulfonyl)-7-(2-oxopyrrolidin-1-yl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate

To a solution of(S)-1-(7-amino-1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)pyrrolidin-2-one(28 mg, 0.7 mmol) in tetrahydrofuran (1 mL) was addedN,N-diisopropylethylamine (56 μL, 0.22 mmol) followed by neopentylchloroformate (16 μL, 0.11 mmol). The reaction was shaken at ambienttemperature for 1 hour, then concentrated onto silica. The residue waspurified by column chromatography eluting with a gradient of methanol indichloromethane to yield the title compound. ¹H NMR (400 Hz, DMSO-d6) δ9.89 (s, 1H), 8.39 (s, 1H), 8.27 (s, 1H), 7.37 (m, 2H,), 7.83 (m, 2H),7.41 (m, 2H), 4.04-3.97 (m, 2H), 3.80 (s, 2H), 3.61 (m, 1H), 3.3-3.2 (m,2H), 2.88 (m, 1H), 2.72 (m, 1H), 2.21 (m, 2H), 1.85 (m, 2H), 0.93 (s,9H).

The enantiomeric compound, Example. No. 76B, was prepared in ananalogous manner.

Example 77—Synthesis of tert-butyl(5-((4-fluorophenyl)sulfonyl)-7-hydroxy-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate(77)

The title compound was prepared according to the procedures describedbelow.

Part I—Synthesis of1-benzyl-7-bromo-3-hydroxy-3,4-dihydro-1,5-naphthyridin-2(1H)-one

To a solution of 1-benzyl-7-bromo-3,4-dihydro-1,5-naphthyridin-2(1H)-one(0.9 g, 2.8 mmol) in anhydrous tetrahydrofuran (3 mL) under a nitrogenatmosphere at −78° C. was added 1M lithium bis(trimethylsilyl)amidesolution in tetrahydrofuran (6.2 mL, 6.2 mmol). After stirring theresulting solution for 5 minutes,(2R,8aS)-(+)-(camphorylsulfonyl)oxaziridine (0.72 g, 3.1 mmol) was addedand the reaction was stirred at −78° C. for 10 minutes, before removingthe cooling bath. The solution was stirred at ambient temperature for 2hours then quenched with 10% citric acid, extracted with ethyl acetate,washed with brine, dried with sodium sulfate, filtered and concentrated.The residue was purified by column chromatography eluting with agradient of 30-100% ethyl acetate in hexanes. The residue was trituratedwith ethyl acetate/hexane mixture. The filtered solids were washed withhexanes and dried to yield the title compound.

Part II—Synthesis of1-benzyl-7-bromo-1,2,3,4-tetrahydro-1,5-naphthyridin-3-ol

To a solution of1-benzyl-7-bromo-3-hydroxy-3,4-dihydro-1,5-naphthyridin-2(1H)-one (0.3g, 0.9 mmol) in anhydrous tetrahydrofuran (6 mL) under nitrogen wasadded borane dimethylsulfide complex (0.36 mL, 3.6 mmol) and thereaction was refluxed for 1 hour. The reaction was next cooled toambient temperature, treated with methanol (3 mL) and refluxed for 10minutes, before being concentrated and dissolved in ethyl acetate,washed with water, brine, dried (Na₂SO₄) and concentrated to yield thetitle compound.

Part III—Synthesis of1-benzyl-7-bromo-3-((tert-butyldimethylsilyl)oxy)-1,2,3,4-tetrahydro-1,5-naphthyridine

To a solution of1-benzyl-7-bromo-1,2,3,4-tetrahydro-1,5-naphthyridin-3-ol (0.26 g, 0.81mmol) in dichloromethane (3 mL) under nitrogen was added 2,6-lutidine(0.24 mL, 2.0 mmol) followed by tert-butyldimethylsilyltrifluoromethanesulfonate (0.21 mL, 0.9 mmol). The reaction was stirredat ambient temperature for two hours. Additional tert-butyldimethylsilyltrifluoromethanesulfonate (0.1 mL, 0.45 mmol) was added and the reactionwas stirred for an additional hour, before the addition of silica. Theresidue was purified by column chromatography eluting with a gradient ofethyl acetate in hexanes to yield the title compound.

Part IV—Synthesis of tert-butyl(5-benzyl-7-((tert-butyldimethylsilyl)oxy)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate

1-benzyl-7-bromo-3-((tert-butyldimethylsilyl)oxy)-1,2,3,4-tetrahydro-1,5-naphthyridine(0.28 g, 0.65 mmol),2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (15 mg, 0.03mmol), tripotassium phosphate (0.41 g, 1.9 mmol), and tert-butylcarbamate (0.11 g, 0.97 mmol) were combined in toluene (5 mL) and water(1 mL). The reaction was degassed, then treated withtris(dibenzylideneacetone)dipalladium(0) (30 mg, 0.03 mmol). Thesolution was refluxed overnight. The solution was cooled, partitionedbetween ethyl acetate and brine, separated, dried, filtered andconcentrated in the presence of silica. The residue was purified bycolumn chromatography eluting with a gradient of ethyl acetate in hexaneto yield the title compound.

Part V—Synthesis of tert-butyl(7-((tert-butyldimethylsilyl)oxy)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate

To a degassed suspension of tert-butyl(5-benzyl-7-((tert-butyldimethylsilyl)oxy)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate(0.11 g, 0.23 mmol) and ammonium formate (0.15 g, 2.3 mmol) under anitrogen atmosphere in methanol (4 mL) was added 10% palladium on carbon(25 mg). The suspension was refluxed for 3 hours. The reaction wascooled to ambient temperature, filtered through CELITE, rinsing withmethanol. Concentrated filtrates were dissolved in ethyl acetate, washedwith water, brine, dried with sodium sulfate (Na₂SO₄) and concentratedto yield the title compound.

Part VI—Synthesis of tert-butyl(7-((tert-butyldimethylsilyl)oxy)-5-((4-fluorophenyl)sulfonyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate

To tert-butyl(7-((tert-butyldimethylsilyl)oxy)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate(85 g, 0.22 mmol) in anhydrous pyridine (1 mL) was added4-fluorobenzenesulfonyl chloride (65 mg, 0.34 mmol) and the resultingsolution was heated to 70° C. for 4 hours. Upon completion, the reactionwas cooled, diluted with ethyl acetate, washed with citric acid, water,brine, dried with sodium sulfate, filtered and concentrated in thepresence of silica. The residue was purified by column chromatographyeluting with a gradient of methanol in dichloromethane to yield thetitle compound.

Part VII—Synthesis of tert-butyl(5-((4-fluorophenyl)sulfonyl)-7-hydroxy-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate

To a solution of tert-butyl(7-((tert-butyldimethylsilyl)oxy)-5-(4-fluorophenyl)sulfonyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate(45 mg, 0.084 mmol) in anhydrous tetrahydrofuran (2 mL) under nitrogenwas added 1M tetrabutylammonium fluoride in tetrahydrofuran (0.17 mL,0.17 mmol). The reaction was stirred at ambient temperature for onehour, then partitioned between ethyl acetate and brine, dried withsodium sulfate, filtered and concentrated in the presence of silica. Theresidue was purified by column chromatography eluting with a gradient ofmethanol in dichloromethane to yield the title compound. ¹H NMR (400 Hz,DMSO-d6) δ 9.55 (s, 1H), 8.29 (m, 1H), 8.14 (s, 1H), 7.85 (m, 2H), 7.38(m, 2H), 5.24 (m, 1H), 3.85 (m, 2H), 3.58 (m, 1H), 2.8 (m, 1H), 2.53 (m,1H), 1.45 (s, 9H).

Example 78—Synthesis of (R)-neopentyl(5-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-7-(hydroxymethyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamateand (S)-neopentyl(5-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-7-(hydroxymethyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate(Example Nos. 78A and 78B)

The title compound was prepared according to the procedures describedbelow.

Part I—Synthesis of1-benzyl-7-bromo-3,4-dihydro-1,5-naphthyridin-2(1H)-one

To 7-bromo-3,4-dihydro-1,5-naphthyridin-2(1H)-one (8.1 g, 35.7 mmol) inN,N-dimethylformamide (50 mL) was added cesium carbonate (23.2 g, 71.4mmol) followed by benzyl bromide (5.1 mL, 42.8 mmol). This mixture wasstirred at 70° C. overnight. The solution was cooled, diluted with ethylacetate, washed with water, brine, dried with sodium sulfate, filteredand concentrated. The residue was recrystallized from ethylacetate/hexanes, and rinsed with hexanes to afford the title compound.

Part II—Synthesis of methyl1-benzyl-7-bromo-2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridine-3-carboxylate

To 1-benzyl-7-bromo-3,4-dihydro-1,5-naphthyridin-2(1H)-one (4.6 g, 14.5mmol) in anhydrous tetrahydrofuran (50 mL) under nitrogen at −78° C. wasadded lithium hexamethyldisilazane (1 M in tetrahydrofuran, 29 mL, 29mmol), and the mixture was stirred for 5 minutes at −78° C. To the anionformed was added methyl chloroformate (1.2 mL, 16 mmol) and this mixturewas stirred at −78° C. for an additional 30 minutes. The mixture wasallowed to warm to ambient temperature, quenched with saturated aqueousammonium chloride, extracted with ethyl acetate, washed with brine,dried with sodium sulfate, filtered and concentrated to yield the titlecompound.

Part III—Synthesis of(1-benzyl-7-bromo-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methanol

To a solution of methyl1-benzyl-7-bromo-2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridine-3-carboxylate(5.35 g, 14.3 mmol) in anhydrous tetrahydrofuran (40 mL) under nitrogenat ambient temperature was carefully added BH₃—SMe₂ (10 M intetrahydrofuran, 5.7 mL, 57 mmol). After this addition, the reaction wasrefluxed for 90 minutes, then cooled to 0° C. and carefully quenchedwith methanol (30 mL), then refluxed for a further 10 minutes. Thesolution was cooled and concentrated. The residue was diluted in ethylacetate, washed with water, brine, dried with sodium sulfate, andconcentrated to yield the title compound.

Part IV—Synthesis of1-benzyl-7-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-1,2,3,4-tetrahydro-1,5-naphthyridine

To a solution of(1-benzyl-7-bromo-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methanol (4.6g, 13.8 mmol) in dichloromethane (50 mL) was added diisopropylethylamine(5.4 mL, 20.7 mmol), tert-butyldimethylsilyl chloride (2.5 g, 16.6 mmol)and catalytic 4-dimethylaminopyridine (0.17 g, 1.4 mmol) and theresulting mixture was stirred at ambient temperature overnight. Thesolution was washed with saturated aqueous ammonium chloride, dried(Na₂SO₄), and concentrated in the presence of silica gel. The residuewas purified by column chromatography eluting with a gradient of 0-30%ethyl acetate in hexanes to yield the title compound.

Part V—Synthesis of5-benzyl-7-(((tert-butyldimethylsilyl)oxy)methyl)-N-(diphenylmethylene)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-amine

A suspension of1-benzyl-7-bromo-3-(((tert-butyldimethylsilyl)oxy)methyl)-1,2,3,4-tetrahydro-1,5-naphthyridine(3.98 g, 8.9 mmol), benzophenone imine (1.8 mL, 10.7 mmol), cesiumcarbonate (4.3 g, 13.3 mmol), X-Phos (0.21 g, 0.44 mmol), andtris(dibenzylideneacetone)dipalladium(0) (0.4 g, 0.44 mmoL) in anhydrous1,4-dioxane (50 mL) was first degassed, then heated at 110° C. undernitrogen overnight. The solution was cooled, diluted with ethyl acetate,filtered through CELITE, and concentrated in the presence of silica gel.The residue was purified by column chromatography eluting with agradient of 5-40% ethyl acetate in hexanes to yield the title compound.

Part VI—Synthesis of5-benzyl-7-(((tert-butyldimethylsilyl)oxy)methyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-amine

To a degassed suspension of5-benzyl-7-(((tert-butyldimethylsilyl)oxy)methyl)-N-(diphenylmethylene)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-amine(3.7 g, 6.8 mmol) and ammonium formate (8.5 g, 135 mmol) under nitrogenin methanol (75 mL) was added 10% palladium on carbon (0.7 g, 0.68mmol). This mixture was refluxed under nitrogen for 2 hours. Thereaction was cooled to ambient temperature and filtered through CELITE,rinsing with methanol. The filtrates were concentrated under reducedpressure, redissolved in ethyl acetate, washed with water, then brine,dried with sodium sulfate, filtered and concentrated in the presence ofsilica gel. Purification by column chromatography eluting with agradient of ethanol in dichloromethane yielded the title compound.

Part VII—Synthesis of tert-butyl(5-benzyl-7-(((tert-butyldimethylsilyl)oxy)methyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate

A mixture of5-benzyl-7-(((tert-butyldimethylsilyl)oxy)methyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-amine(3.83 g, 10 mmol), triethylamine (2.02 g, 20 mmol), and di-tert-butyldicarbonate (2.73 g, 12.5 mmol) in dichloromethane (50 mL) was stirredat room temperature for 2 days. The reaction mixture was partitionedbetween dichloromethane and water. The aqueous layer was re-extractedwith dichloromethane, and the combined organic layers were dried(Na₂SO₄) and concentrated to afford the title compound, which was usedwithout further purification.

Part VIII—Synthesis of[7-(tert-butyl-dimethyl-silanyloxymethyl)-5,6,7,8-tetrahydro-[1,5]naphthyridin-3-yl]-carbamicacid tert-butyl ester

[5-Benzyl-7-(tert-butyl-dimethyl-silanyloxymethyl)-5,6,7,8-tetrahydro-[1,5]naphthyridin-3-yl]-carbamicacid tert-butyl ester (5.9 g, 12.2 mmol) was dissolved in methanol (100mL) and 10% Pd/C catalyst (1.0 g) was added, followed by ammoniumformate (5 g). The mixture was heated at reflux for 24 hours. The cooledmixture was filtered through a pad of CELITE and the filtrate wasevaporated. The residue was purified by SiO₂ chromatography to affordthe title compound. LC/MS (ESI) m/z 394.4. This material was separatedby chiral SPC chromatography into its two enantiomers. Compounds derivedfrom the first enantiomer to elute are named with an “A” in the name.The following experimental procedures are illustrative of the chemistryemployed separately for each of the two enantiomers.

Part IX—Synthesis of[7-(tert-butyl-dimethyl-silanyloxymethyl)-5-(4-fluorobenzenesulfonyl)-5,6,7,8-tetrahydro-[1,5]naphthyridin-3-yl]-carbamicacid tert-butyl ester

To a solution[7-(tert-butyl-dimethyl-silanyloxymethyl)-5,6,7,8-tetrahydro-[1,5]naphthyridin-3-yl]-carbamicacid tert-butyl ester (0.394 g, 1 mmol), 4-dimethylaminopyridine (0.061g, 0.5 mmol) in pyridine (15 mL) was added1-difluoromethyl-3-methyl-1H-pyrazole-4-sulfonyl chloride (0.277 g, 1.2mmol). The reaction was heated at 60° C. for 4 hours. The reaction wascooled and partitioned between ethyl acetate and water. The organiclayer was washed with brine, dried (Na₂SO₄) and concentrated. Theresidue was purified by chromatography on silica gel to give[7-(tert-butyl-dimethyl-silanyloxymethyl)-5-(1-difluoromethyl-3-methyl-1H-pyrazole-4-sulfonyl)-5,6,7,8-tetrahydro-[1,5]naphthyridin-3-yl]-carbamicacid tert-butyl ester. LC/MS(ESI) m/z 588.5.

The enantiomeric compound was prepared in an analogous manner.

Example 79—Preparation of Additional Sulfonamides from7-(hydroxymethyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamates

The compounds in Table 25 below were prepared based on the experimentalprocedures described in Examples 77 and 78 and elsewhere in the detaileddescription, and can be achieved by one of skill in the art in light ofthe present disclosure.

TABLE 25 Ex. Observed No. Structure Name m/z 79A

tert-butyl (7-(hydroxymethyl)-5-(m-tolylsulfonyl)-5,6,7,8-tetrahydro-1,5- naphthyridin-3-yl)carbamate 434(M + H)⁺ 79B

tert-butyl (5-((3,4-difluorophenyl)sulfonyl)-7-(hydroxymethyl)-5,6,7,8-tetrahydro-1,5- naphthyridin-3-yl)carbamate 456(M + H)⁺ 79C

(R or S)-neopentyl (5-((4- fluorophenyl)sulfonyl)-7-(hydroxymethyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3- yl)carbamate 452 (M + H)⁺ 79D

(S or R)-neopentyl (5-((4- fluorophenyl)sulfonyl)-7-(hydroxymethyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3- yl)carbamate 452 (M + H)⁺

Example 80—Synthesis of neopentyl((S)-5-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate(Examples 80A and 80B)

The title compound was prepared according to the procedures describedbelow.

Part I—Synthesis of(R)-(1-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-7-(((neopentyloxy)carbonyl)amino)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methylmethanesulfonate

To a solution (R)-neopentyl(5-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-7-(hydroxymethyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate(0.28 g, 0.59 mmol) in dichloromethane (5 mL) was added triethylamine(0.248 mL, 1.77 mmol) and methanesulfonic acid anhydride (0.153 g, 0.88mmol). The mixture was stirred at room temperature for four hours, thenconcentrated, and the residue was partitioned between ethyl acetate andwater. The organic layer was dried (Na₂SO₄) and concentrated to affordthe title compound.

Part II—Synthesis of neopentyl((S)-5-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-7-(((R)-3-hydroxypyrrolidin-1-yl)methyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate

A mixture(R)-(1-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-7-(((neopentyloxy)carbonyl)amino)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methylmethanesulfonate (0.10 g, 0.18 mmol) and (R)-pyrrolidine-3-ol (31.3 mg,0.36 mmol) in THF with triethylamine (10 uL) was heated at 70° C. for 12hours. The reaction mixture was diluted with dichloromethane and washedwith water. The organic layer was dried (Na₂SO₄) and concentrated. Theresidue was purified by column chromatography eluting withdichloromethane/MeOH/triethylamine (89:10:1) to give the title compound,Example No. 80A. LRMS (ESI) calculated for C₂₄H₃₅F₂N₆O₅S (M+H)⁺: 557,Found: 557.

Ex. No. 80B was prepared in an analogous manner using the enantiomer ofthe starting alcohol. LRMS (ESI) calculated for C₂₄H₃₅F₂N₆O₅S (M+H)⁺:557, Found: 557.

Example 81—Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl ((R orS)-4-((3,4-difluorophenyl)sulfonyl)-2-((S orR)-2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(Examples 81A, 81B, and 81C)

To a solution of (R and S)-1,1,1-trifluoro-2-methylpropan-2-yl4-(3,4-difluorophenylsulfonyl)-2-(2,2,2-trifluoroacetyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-ylcarbamate(260 mg, 0.47 mmol) in 10 mL of MeOH was added NaBH₄ (35 mg, 0.93 mmol)and the resulting mixture was stirred at room temperature for 2 hours.Water was added and the mixture was extracted with EtOAc. The organicphase was washed with brine, dried over Na₂SO₄ and filtered. Thefiltrate was concentrated in vacuo to give the crude mixture ofdiastereomers as a yellow solid. LCMS (ESI): calculated forC₂₁H₁₇F₈N₂O₆S [M+H]⁺: 579, found [M+H]⁺: 579.

The mixture of diastereomers was separated by chiral SFC to afford threeeluents: First Isomer (Peak 1, Example 81A): as a white solid, ¹H-NMR(MeOD, 400 MHz) δ 7.98 (1H, s), 7.72-7.74 (1H, m), 7.58 (1H, br s),7.47-7.51 (1H, m), 7.08-7.11 (1H, m), 6.78 (1H, d, J=8.8 Hz), 4.40-4.43(1H, m), 4.08-4.11 (1H, m), 3.62-3.65 (1H, m), 3.51-3.54 (1H, m), 1.77(6H, s); Second Isomer (Peak 2, Example 81B): as a white solid, ¹H-NMR(MeOD, 400 MHz) δ 7.97 (1H, s), 7.79-7.81 (1H, m), 7.60-7.62 (1H, m),7.45-7.49 (1H, m), 7.09-7.12 (1H, m), 6.80-7.00 (1H, m), 4.45-4.50 (1H,m), 4.21-4.24 (1H, m), 3.68-3.70 (1H, m), 3.38-3.42 (1H, m), 1.77 (6H,s); Third Isomer (Peak 3, Example 81C): as a white solid, ¹H-NMR (MeOD,400 MHz) δ 7.97 (1H, s), 7.79-7.81 (1H, m), 7.60-7.62 (1H, m), 7.45-7.49(1H, m), 7.09-7.12 (1H, m), 6.80-7.00 (1H, m), 4.45-4.50 (1H, m),4.21-4.24 (1H, m), 3.68-3.70 (1H, m), 3.38-3.42 (1H, m), 1.77 (6H, s).

The compounds in Table 26 below were prepared based on the methodsdescribed in Example X and elsewhere in the description, and can beachieved by one of skill in the art in light of the present disclosure.

TABLE 26 Ex. Observed No. Structure Name m/z 81D

1,1,1-trifluoro-2-methylpropan-2-yl ((R or S)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-((S or R)- 2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 612 (M + NH₄)+ 81E

1,1,1-trifluoro-2-methylpropan-2-yl ((R or S)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-((S or R)- 2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 595 (M + H)+ 81F

1,1,1-trifluoro-2-methylpropan-2-yl ((R or S)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-((S or R)- 2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 595 (M + H)+ 81G

1,1,1-trifluoro-2-methylpropan-2-yl ((S and R)-4-((4-fluorophenyl)sulfonyl)-2-((S and R)-2,2,2-trifluoro-1-hydroxyethyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 561 (M + H)+

Example 82—Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl((S)-2-((R)-1-amino-2,2,2-trifluoroethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate,1,1,1-trifluoro-2-methylpropan-2-yl((S)-2-((S)-1-amino-2,2,2-trifluoroethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate,1,1,1-trifluoro-2-methylpropan-2-yl((R)-2-((R)-1-amino-2,2,2-trifluoroethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate,1,1,1-trifluoro-2-methylpropan-2-yl((R)-2-((S)-1-amino-2,2,2-trifluoroethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(Examples 82A, 82B, 82C, and 82D)

Step 1—Preparation of (S and R)-2,2,2-trifluoro-1-((R andS)-4-((4-fluorophenyl)sulfonyl)-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyltrifluoromethanesulfonate

To a solution of 1,1,1-trifluoro-2-methylpropan-2-yl ((S andR)-4-((4-fluorophenyl)sulfonyl)-2-((S andR)-2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(600 mg, 1.07 mmol) in 25 mL/2.5 mL of DCM/pyridine was added Tf₂O (480mg, 1.70 mmol) at 0° C. and the resulted mixture was stirred at 0° C.for 1 hour. 1 N HCl was then added and the mixture was extracted 3× withDCM. The combined organic layers were washed with brine, dried overNa₂SO₄ and filtered. The filtrate was concentrated in vacuo to give thecrude title compound as a yellow oil, which was used in the next stepwithout further purification. ¹H-NMR (MeOD, 400 MHz) δ 7.95-7.97 (1H,m), 7.75-7.82 (2H, m), 7.28-7.33 (2H, m), 7.18-7.19 (1H, m), 6.82-6.84(1H, m), 5.92-6.01 (1H, m), 4.51-4.57 (1H, m), 3.86-3.91 (1H, m),3.36-3.44 (1H, m), 1.77 (6H, s).

Step 2—Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl ((R andS)-2-((S andR)-1-azido-2,2,2-trifluoroethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (S and R)-2,2,2-trifluoro-1-((R andS)-4-((4-fluorophenyl)sulfonyl)-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyltrifluoromethanesulfonate (600 mg, 0.87 mmol) in 20 ml, of DMSO wasadded NaN₃ (120 mg, 1.85 mmol) and then the resulted mixture was stirredat room temperature for 16 hours. Water was added and the mixtureextracted 3× with EtOAc. The aqueous layer was treated with H₂O₂,followed by Na₂SO₃ before being discarded. The organic layer was washedwith water, brine, dried over Na₂SO₄ and filtered. The filtrate wasconcentrated in vacuo to give the title compound as white solid. ¹H-NMR(MeOD, 400 MHz) δ 7.97 (s, 1H), 7.79-7.82 (m, 2H), 7.21-7.31 (m, 2H),7.14-7.17 (m, 1H), 6.77-6.79 (m, 1H), 4.39-4.49 (m, 1H), 4.35-4.38 (m,1H), 3.72-3.75 (m, 1H), 3.40-3.47 (m, 1H), 1.77 (s, 6H).

Step 3—Preparation of Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl((S)-2-((R)-1-amino-2,2,2-trifluoroethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate,1,1,1-trifluoro-2-methylpropan-2-yl((S)-2-((S)-1-amino-2,2,2-trifluoroethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate,1,1,1-trifluoro-2-methylpropan-2-yl((R)-2-((R)-1-amino-2,2,2-trifluoroethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate,1,1,1-trifluoro-2-methylpropan-2-yl((R)-2-((S)-1-amino-2,2,2-trifluoroethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

A solution of 1,1,1-trifluoro-2-methylpropan-2-yl ((R and S)-2-((S andR)-1-azido-2,2,2-trifluoroethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(300 mg, 0.51 mmol) and one drop of NH₄OH in 30 mL of MeOH was chargedwith 150 mg of Pd/C (wet) and the reaction was stirred at roomtemperature for 16 hours under H₂ balloon atmosphere. The reactionmixture was filtered through CELITE and the filtrate was concentrated togive the crude product as a yellow solid. LCMS (ESI): calculated forC₂₁H₂₁F₇N₃O₅S [M+H]⁺: 560, found: 560.

The mixture was separated by chiral SFC (Chiralcel OD-3 150×4.6 mm I.D.,3 um; Mobile phase: methanol (0.05% DEA) in CO₂ from 5% to 40%) toafford 4 isomers. First Isomer (Peak 1, Example 82A): ¹H-NMR (MeOD, 400MHz) δ 7.98 (1H, s), 7.79-7.83 (1H, m), 7.25-7.30 (2H, m), 7.10-7.13(1H, m), 6.76-6.78 (1H, m), 4.47-4.51 (1H, m), 3.56-3.59 (1H, m),3.43-3.49 (2H, m), 1.77 (6H, s); Second Isomer (Peak 2, Example 82B):¹H-NMR (MeOD, 400 MHz) δ 7.98 (1H, s), 7.79-7.83 (2H, m), 7.25-7.30 (2H,m), 7.10-7.13 (1H, m), 6.76-6.78 (1H, m), 4.47-4.51 (1H, m), 3.56-3.59(1H, m), 3.43-3.49 (2H, m), 1.77 (6H, s); Third Isomer (Peak 3, Example82C): ¹H-NMR (MeOD, 400 MHz) δ 7.97 (1H, s), 7.78-7.81 (2H, m),7.25-7.29 (2H, m), 7.13-7.15 (1H, m), 6.79-6.81 (1H, m), 4.37-4.41 (1H,m), 3.43-3.58 (3H, m, 3H), 1.77 (6H, s); Fourth Isomer (Peak 4, Example82D): ¹H-NMR (MeOD, 400 MHz) δ 7.97 (1H, s), 7.78-7.81 (2H, m),7.25-7.29 (2H, m), 7.13-7.15 (1H, m), 6.79-6.81 (1H, m), 4.37-4.41 (1H,m), 3.43-3.58 (3H, m), 1.77 (6H, s).

Example 83—Preparation of (S)-tert-butyl(2-(2-(ethylsulfonyl)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(Example 83)

Step 1—Preparation of (S)-methyl2-(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate

To a mixture of (S)-methyl2-(6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate(200 mg, 0.531 mmol) in THF (3 mL) was added3-(trifluoromethyl)benzene-1-sulfonyl chloride (195 mg, 0.797 mmol) andpyridine (3 mL). The reaction mixture was stirred at 20° C. for 2 hours,then diluted with water (20 mL) and extracted with ethyl acetate (3×15mL). The organic layers were separated, combined, dried over anhydrousmagnesium sulfate, filtered and concentrated in vacuo and the residualoil was purified by prep-TLC (petroleum ether/ethyl acetate=3:1) toafford the title compound as a white solid. LCMS (ESI) calculated forC₂₃H₂₆F₃N₂O₇S [M+H]⁺: 531.1, found: 553.2.

Step 2—Preparation of (S)-tert-butyl(2-(2-hydroxyethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (S)-methyl2-(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate (200 mg, 0.377mmol) in dry methanol (10 mL) was added sodium borohydride (83 mg, 2.262mmol) at 0° C. The reaction was stirred at 50° C. for 12 hours, thenquenched with aqueous ammonium chloride (30 mL) and extracted with ethylacetate (3×50 mL). The combined organic layers were dried over sodiumsulfate and evaporated to dryness. The crude product was purified bycolumn chromatography (petroleum ether/ethyl acetate=30:1 to 1:1) togive the title compound as a white solid. LCMS (ESI) calculated forC₂₂H₂₅F₃N₂O₆SNa [M+Na]⁺: 525.1, found: 525.2; ¹H NMR (Methanol-d₄, 400MHz) δ 7.98-8.04 (3H, m), 7.91 (1H, d, J=8.0 Hz), 7.68-7.73 (1H, m),6.98 (1H, d, J=7.2 Hz), 6.67 (1H, d, J=8.4 Hz), 4.41-4.44 (1H, m),3.61-3.66 (3H, m), 3.19-3.25 (1H, m), 1.69-1.74 (2H, m), 1.51 (9H, s).

Step 3—Preparation of(S)-2-(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl methanesulfonate

To a solution of (S)-tert-butyl(2-(2-hydroxyethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(296 mg, 0.589 mmol), triethylamine (0.411 ml, 2.95 mmol) in drydichloromethane (10 mL) at 0° C. was added methanesulfonyl chloride(1350 mg, 11.78 mmol). The reaction mixture was stirred at 20° C. for 4hours, then quenched with water (20 mL). The aqueous layer was extractedwith dichloromethane (3×20 mL). The organic layer was dried over sodiumsulfate, evaporated, and the residue was purified by columnchromatography (petroleum ether/ethyl acetate=20:1 to 4:1) to give thetitle compound as a colorless oil. LCMS (ESI) calculated forC₂₃H₂₇F₃N₂O₈S₂Na [M+Na]⁺: 603.1, found: 603.1.

Step 4—Preparation of (S)-tert-butyl(2-(2-(ethylthio)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of(S)-2-(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethylmethanesulfonate (160 mg, 0.276 mmol) in EtOH (10 mL) at 0° C. was addedsodium ethanethiolate (116 mg, 1.378 mmol). The reaction mixture wasstirred at 80° C. for 5 hours, then poured into water and extracted withethyl acetate (3×30 mL). The organic layer was dried over sodiumsulfate, evaporated, and the residue was purified by columnchromatography (petroleum ether/ethyl acetate=20:1 to 5:1) to give thetitled compound as a colorless oil. LCMS (ESI) calculated forC₂₄H₃₀F₃N₂O₅S₂[M+H]⁺: 547.1, found: 547.1.

Step 5—Preparation of (S)-tert-butyl(2-(2-(ethylsulfonyl)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (S)-tert-butyl(2-(2-(ethylthio)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(140 mg, 0.256 mmol) in dichloromethane (10 mL) at 0° C. was addedmetachloroperbenzoic acid (133 mg, 0.768 mmol). The reaction mixture wasstirred at 15° C. for 2 hours, then poured into water and extracted withdichloromethane (3×30 mL). The organic layer was dried over sodiumsulfate, evaporated, and the residue was purified by columnchromatography (petroleum ether/ethyl acetate=20:1 to 3:1) to give thetitled compound as a colorless oil. LCMS (ESI) calculated forC₂₄H₂₉F₃N₂O₇S₂Na [M+Na]⁺: 601.1, found: 601.0; ¹H NMR (Methanol-d₄, 400MHz) δ 8.02-8.11 (3H, m), 7.93 (1H, d, J=8.0 Hz), 7.72-7.77 (1H, m),7.01 (1H, d, J=6.8 Hz), 6.73 (1H, d, J=8.4 Hz), 4.44 (1H, d, J=14.0 Hz),3.71 (1H, brs), 3.08-3.34 (5H, m), 2.12-2.17 (1H, m), 1.97-2.03 (1H, m),1.53 (9H, s), 1.33 (3H, t, J=7.6 Hz).

Example 84—Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-(ethylsulfonyl)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(Example 84)

Step 1—Preparation of(S)-2-(2-(ethylsulfonyl)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-amine

To a solution of (S)-tert-butyl(2-(2-(ethylsulfonyl)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(140 mg, 0.242 mmol) in dichloromethane (5 mL) was added trifluoroaceticacid (2 mL) at 0° C. The reaction mixture was stirred at 15° C. for 2hours, then evaporated to give the crude title compound as a colorlessoil. LCMS (ESI) calculated for C₁₉H₂₂F₃N₂O₅S₂[M+H]⁺: 479.1, found:479.2.

Step 2—Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-(ethylsulfonyl)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

A mixture of(S)-2-(2-(ethylsulfonyl)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-amine(50 mg, 0.104 mmol) and3-methyl-1-(((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)-1H-imidazol-3-iumiodide (49.6 mg, 0.209 mmol) in DMSO (3 mL) was stirred at 15° C. for 1hour. The reaction mixture was directly purified by Prep-HPLC, elutingwith Acetonitrile/Water+0.10% TFA, to give the titled compound as awhite solid. LCMS (ESI) calculated for C₂₄H₂₇F₆N₂O₇S₂ [M+H]⁺: 633.1,found: 633.0; ¹H NMR (Methanol-d₄, 400 MHz) δ 8.06-8.13 (3H, m), 7.92(1H, d, J=8.0 Hz), 7.71 (1H, t, J=8.0 Hz), 7.01 (1H, d, J=6.8 Hz), 6.73(1H, d, J=8.8 Hz), 4.43 (1H, d, J=12.4 Hz), 3.75 (1H, brs), 3.04-3.35(5H, m), 2.12-2.16 (1H, m), 1.97-2.02 (1H, m), 1.75 (6H, s), 1.30 (3H,t, J=7.6 Hz).

Example 85—Synthesis of 1,1,1-trifluoro-2-methylpropan-2-yl((2S,3R)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3-methyl-2-(((N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(Example 85)

Step 1—Synthesis of (R and S)-ethyl3-methyl-6-nitro-2H-benzo[b][1,4]oxazine-2-carboxylate

Into a 2000-mL 3-necked round-bottom flask was placed a solution of2-amino-4-nitrophenol (80 g, 519.06 mmol, 1.00 equiv) in 1,4-dioxane(1000 mL), potassium carbonate (143 g, 1.03 mol, 2.00 equiv) and ethyl2-chloro-3-oxobutanoate (170 g, 1.03 mol, 2.00 equiv). The resultingsolution was stirred for 2 h at 100° C. in an oil bath, then cooled to25° C., diluted with 3000 mL of H₂O and stirred for 1 h at roomtemperature. The solids were collected by filtration and the crude solidwas dried and stirred in 600 mL of ether for 2 h at room temperature.The solids were collected by filtration to yield ethyl3-methyl-6-nitro-2H-1,4-benzoxazine-2-carboxylate as a red solid.

Step 2—Synthesis of ((2S,3S,2S,3R,2R,3S and2R,3R)-3-methyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methanol

Into a 3000-mL 3-necked round-bottom flask was placed a solution of (Rand S)-ethyl 3-methyl-6-nitro-2H-benzo[b][1,4]oxazine-2-carboxylate (105g, 397.37 mmol, 1.00 equiv) in ethanol (1500 mL), followed by theaddition of NaBH₄ (44 g, 1.16 mol, 3.00 equiv), in portions over 30 min.The resulting solution was stirred for 3 h at 40° C., then quenched bythe addition of 1500 mL of water. The resulting mixture was extractedwith 3×1500 mL of ethyl acetate and the combined organic layers washedwith 3×1000 mL of saturated brine, dried over anhydrous sodium sulfateand concentrated under vacuum to afford the title compound as a redsyrup.

Step 3—Synthesis tert-butyl((2R,3R)-2-(hydroxymethyl)-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamateand tert-butyl((2S,3S)-2-(hydroxymethyl)-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

Into a 2000-mL round-bottom flask was placed a solution of(3-methyl-6-nitro-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methanol (80 g,356.80 mmol, 1.00 equiv) in ethyl acetate (1200 mL), Palladium on carbon(8 g, 0.10 equiv) and (Boc)₂O (116 g, 531.50 mmol, 1.50 equiv). Theresulting solution was stirred for 4 h at 40° C. in an oil bath under anatmosphere of hydrogen, then filtered. The filtrate was concentratedunder vacuum and the crude product was applied onto a silica gel columnand eluted with ethyl acetate/petroleum ether (5:1 to 1:1). Prep-SFCseparation was conducted under the following conditions: Column,ChiralPak IC, 5×25 cm, Sum; mobile phase, CO₂ (65%), IPA (with 0.2% DEA)(35%). Detector, UV 220 nm to afford tert-butylN-[(2S,3S)-2-(hydroxymethyl)-3-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbamateas a white solid and of tert-butylN-[(2R,3R)-2-(hydroxymethyl)-3-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbamateas a white solid.

tert-butyl((2S,3S)-2-(hydroxymethyl)-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

LC-MS (ES, m/z) calculated for C₁₅H₂₃N₂O₄ [M+H]⁺: 295, found 295 [α]_(D)²⁰=+51.3 (c=1.0 g/100 mL MeOH); ¹H-NMR (300 MHz, CDCl₃, ppm): δ 6.93 (s,1H), 6.75-6.22 (d, 1H), 6.46-6.42 (m, 1H), 6.28 (s, 1H), 4.25-4.20 (m,1H), 3.87-3.80 (m, 1H), 3.73-3.69 (m, 1H), 3.61-3.58 (m, 1H), 1.49 (s,9H), 1.20-1.17 (d, 3H).

tert-butyl((2R,3R)-2-(hydroxymethyl)-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

LC-MS (ES, m/z) calculated for C₁₅H₂₃N₂O₄ [M+H]⁺: 295, found 295 [α]_(D)²⁰=−51.1 (c=1.0 g/100 mL MeOH); ¹H-NMR (300 MHz CDCl₃, ppm): δ 6.93 (s,1H), 6.75-6.22 (d, 1H), 6.46-6.42 (m, 1H), 6.28 (s, 1H), 4.25-4.20 (m,1H), 3.87-3.80 (m, 1H), 3.73-3.69 (m, 1H), 3.61-3.58 (m, 1H), 1.49 (s,9H), 1.20-1.17 (d, 3H).

Step 4—Synthesis((2R,3R)-6-((tert-butoxycarbonyl)amino)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl1-(difluoromethyl)-3-methyl-1H-pyrazole-4-sulfonate

To a microwave vial equipped with a stir bar was added tert-butyl((2R,3R)-2-(hydroxymethyl)-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(500 mg, 1.699 mmol), 1-(difluoromethyl)-3-methyl-1H-pyrazole-4-sulfonylchloride (1959 mg, 8.49 mmol) and pyridine (10 mL). The vial was sealedand the reaction heated to 60° C. for 1 h. Upon completion, the reactionmixture was extracted with 3×IPA/CHCl₃ (1:3 v/v) and NaHCO₃ and thecombined organic layers were dried over magnesium sulfate, filtered, andconcentrated under reduced pressure. The crude product was purified byflash column chromatography using 100% hexanes to 40% ethyl acetategradient to afford the title product as a white solid. LCMS (ESI):calculated for C₂₁H₂₃F₄N₆O₈S₂[M-tBu+H]⁺: 627, found: 627.

Step 5—Synthesis tert-butyl((2S,3R)-2-(azidomethyl)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a microwave vial equipped with a stir bar was added((2R,3R)-6-((tert-butoxycarbonyl)amino)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl1-(difluoromethyl)-3-methyl-1H-pyrazole-4-sulfonate (950 mg, 1.392mmol), DMF (16 ml) and sodium azide (452 mg, 6.96 mmol). The vial wassealed and the reaction heated to 80° C. for 1 h. Upon completion, thereaction mixture was extract 3×IPA/CHCl₃ (1:3, v/v) and saturatedNaHCO₃, and the combined organic layer dried and concentrated to affordthe crude title compound, which was taken forward without furtherpurification. LCMS (ESI): calculated for C₁₆H₁₈F₂N₇O₅S [M-tBu+H]⁺: 458,found: 458.

Step 6—Synthesis of tert-butyl((2S,3R)-2-(aminomethyl)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a flask equipped with a stir bar was added tert-butyl((2S,3R)-2-(azidomethyl)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(715 mg, 1.392 mmol), ethyl acetate (21 ml), MeOH (7 ml) and 10% Pd/C(44.5 mg, 0.418 mmol) under a strong flow of nitrogen. The reactionflask was purged 3× with hydrogen and stirred under H₂ balloonatmosphere for 3 h. Upon completion, the reaction mixture was filteredthrough CELITE and the filtrate concentrate under vacuum. The crudeproduct was taken forward without further purification. LCMS (ESI):calculated for C₁₆H₂₀F₂N₅O₅S [M-tBu+H]⁺: 432, found: 432.

Step 7—Synthesis tert-butyl((2S,3R)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3-methyl-2-(((N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a microwave vial equipped with a stir bar was added tert-butyl((2S,3R)-2-(aminomethyl)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(30 mg, 0.062 mmol), DIEA (0.043 mL, 0.246 mmol), and DCM (1 mL),followed by methylsulfamoyl chloride (15.95 mg, 0.123 mmol). Thereaction was allowed to stir at room temperature for 1 h and thenextracted with 3× ethyl acetate and saturated NaHCO₃. The combinedorganic layer was dried over magnesium sulfate, filtered andconcentrated under reduced pressure to afford the title compound, whichwas taken forward without further purification. LCMS (ESI): calculatedfor C₁₇H₂₃F₂N₆O₇S₂ [M-tBu+H]⁺: 525, found: 525.

Step 8—Synthesis of 1,1,1-trifluoro-2-methylpropan-2-yl((2S,3R)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3-methyl-2-(((N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

Tert-butyl((2S,3R)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3-methyl-2-(((N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(35.7 mg, 0.061 mmol) was stirred with 4M HCl in dioxane (0.461 ml,1.845 mmol) for 1 h at room temperature. Upon completion, the reactionwas concentrated and dried under vacuum to afford the intermediateaniline, which was next dissolved in DMF (1.0 mL) before the addition of1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate (27.3 mg,0.123 mmol). The reaction mixture was heated to 80° C. for 1 h, thenquenched by the addition of 3 drops of water. The resulting mixture wasdissolved in 2 mL of DMSO, filtered and directly purified by reversephase HPLC (MeCN/water using TFA buffer) to afford the desired productas a white solid. LCMS (ESI): calculated for C₂₁H₂₈F₅N₆O₇S₂[M+H]⁺: 635,found: 635. ¹H-NMR (CDCl₃, 400 MHz) δ 9.75 (s, 1H), 8.68 (s, 1H), 7.90(m, 1H), 7.63 (t, 1H), 7.28 (m, 1H), 7.18 (m, 1H), 6.80 (m, 2H), 4.57(m, 1H), 3.60 (m, 1H), 2.90-3.05 (m, 2H), 2.40 (m, 3H), 2.05 (s, 3H),1.68 (s, 6H), 0.98 (m, 3H).

Example 86—Synthesis of 1,1,1-trifluoro-2-methylpropan-2-ylN-[(2S,3R)-2-[(1S)-1-[[(benzyloxy)carbonyl]amino]ethyl]-4-[(3,4-difluorobenzene)sulfonyl]-3-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbamate(Example 86)

Step 1—Synthesis of(2S,3S,4R)-4-((tert-butoxycarbonyl)amino)-3-((tert-butyldimethylsilyl)oxy)-2-methylpentanoicAcid

Into a 500-mL 3-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed a solution of known (JACS,2003, 8218)(2S,3S,4R)-4-[[(tert-butoxy)carbonyl]amino]-3-hydroxy-2-methylpentanoicacid (9.88 g, 39.95 mmol, 1.00 equiv) in dichloromethane (200 mL),2,6-dimethylpyridine (12.8 g, 119.46 mmol, 3.00 equiv). This wasfollowed by the addition of TBSOTf (26.4 g, 100.00 mmol, 2.50 equiv)dropwise with stirring at −78° C. The resulting solution was stirred for60 min at −78° C. The reaction was then quenched by the addition ofwater/ice. The resulting solution was extracted with 3×200 mL of ethylacetate and the organic layers combined and concentrated under vacuum.The resulting crude intermediate was diluted with 150 mL of methanol.Then 50 mL of K₂CO₃ (0.5 M) was added and stirring was continued for anadditional 60 min at room temperature. The pH value of the solution wasadjusted to 2 with hydrogen chloride (1 N) and the resulting mixture wasextracted with 3×300 mL of ethyl acetate. The organic layers werecombined and concentrated under vacuum. The residue was applied onto asilica gel column with ethyl acetate/petroleum ether (1:1) to afford(2S,3S,4R)-4-[[(tert-butoxy)carbonyl]amino]-3-[(tert-butyldimethylsilyl)oxy]-2-methylpentanoicacid as a white solid. ¹H-NMR (CDCl₃, 400 MHz) δ 4.48 (br s, 1H), 4.05(m, 1H), 3.78 (m, 1H), 2.63 (m, 1H), 1.25-1.10 (m, 8H), 0.90 (m, 13H),0.30 (m, 8H).

Step 2—Synthesis of benzyl tert-butyl((2R,3S,4S)-3-((tert-butyldimethylsilyl)oxy)pentane-2,4-diyl)dicarbamate

Into a 50-mL round-bottom flask purged and maintained under an inertatmosphere of nitrogen, was placed a solution of(2S,3S,4R)-4-[[(tert-butoxy)carbonyl]amino]-3-[(tert-butyldimethylsilyl)oxy]-2-methylpentanoicacid (1.8 g, 4.98 mmol, 1.00 equiv) in toluene (20 mL), DPPA (1.38 g,5.01 mmol, 1.00 equiv) and TEA (1.0 g, 9.88 mmol, 2.00 equiv). Theresulting solution was stirred for 2 h at 60° C. Then phenylmethanol(1.62 g, 14.98 mmol, 3.00 equiv) and TEA (1.0 g, 9.88 mmol, 2.0 eq.)were added and stirring was continued for an additional 3 days at 90° C.The reaction was then quenched by the addition of water. The resultingmixture was extracted with 3×50 mL of ethyl acetate and the organiclayers combined, washed with 2×30 mL of brine, dried and concentrated.The crude product was applied onto a silica gel column with ethylacetate/petroleum ether (1:10) to afford tert-butylN-[(2S,3S,4S)-4-[[(benzyloxy)carbonyl]amino]-3-[(tert-butyldimethylsilyl)oxy]pentan-2-yl]carbamateas a colorless oil, which was used in the next step without furtherpurification.

Step 3—Synthesis of benzyl tert-butyl((2R,3S,4S)-3-hydroxypentane-2,4-diyl)dicarbamate

Into a 50-mL round-bottom flask, was placed a solution of tert-butylN-[(2R,3S,4R)-4-[[(benzyloxy)carbonyl]amino]-3-[(tert-butyldimethylsilyl)oxy]pentan-2-yl]carbamate(1.3 g, 2.79 mmol, 1.00 equiv) in tetrahydrofuran (20 mL), TBAF (1.46 g,5.58 mmol, 2.00 equiv). The resulting solution was stirred for 2 h atroom temperature, then concentrated under vacuum. The crude product wasapplied onto a silica gel column with ethyl acetate/petroleum ether(1:2) to afford tert-butylN-[(2S,3S,4R)-4-[[(benzyloxy)carbonyl]amino]-3-hydroxypentan-2-yl]carbamateas a colorless oil, which was used in the next step without furtherpurification.

Step 4—Synthesis of benzyl tert-butyl((2R,3S,4S)-3-(2-bromo-4-nitrophenoxy)pentane-2,4-diyl)dicarbamate

Into a 50-mL 3-necked round-bottom flask, was placed tert-butylN-[(2R,3S,4S)-4-[[(benzyloxy)carbonyl]amino]-3-hydroxypentan-2-yl]carbamate(950 mg, 2.70 mmol, 1.00 equiv), followed by the addition of sodiumhydride (324 mg, 8.10 mmol, 3.00 equiv) in several batches at 0° C. Tothis was added tetrahydrofuran (20 mL) and2-bromo-1-fluoro-4-nitrobenzene (768 mg, 3.49 mmol, 1.30 equiv). Theresulting solution was stirred for 30 min at 0° C. and at roomtemperature for 12 h. The reaction was then quenched by the addition of20 mL of water/ice and the resulting mixture was extracted with 3×30 mLof ethyl acetate. The crude product was applied onto a silica gel columnwith ethyl acetate/petroleum ether (1:20-1:1) to afford tert-butylN-[(2R,3S,4S)-4-[[(benzyloxy)carbonyl]amino]-3-(2-bromo-4-nitrophenoxy)pentan-2-yl]carbamateas a yellow solid.

Step 5—Synthesis of benzyl((2S,3R,4R)-4-amino-3-(2-bromo-4-nitrophenoxy)pentan-2-yl)carbamate

Into a 25-mL round-bottom flask was placed a solution of tert-butylN-[(2R,3S,4S)-4-[[(benzyloxy)carbonyl]amino]-3-(2-bromo-4-nitrophenoxy)pentan-2-yl]carbamate(450 mg, 0.81 mmol, 1.00 equiv) in dichloromethane (10 mL) and CF₃COOH(3 mL). The resulting solution was stirred for 2 h at room temperature,then quenched with saturated NaHCO₃ (aq.). The resulting mixture wasextracted with DCM (20 mL×3) and the combined organic layersconcentrated under vacuum to afford benzylN-[(2S,3R,4R)-4-amino-3-(2-bromo-4-nitrophenoxy)pentan-2-yl]carbamate asa yellow solid, which was carried forward without further purification.

Step 6—Synthesis of benzyl((2S,3S,4R)-3-(2-bromo-4-nitrophenoxy)-4-(3,4-difluorophenylsulfonamido)pentan-2-yl)carbamate

Into a 25-mL round-bottom flask was placed benzylN-[(2S,3R,4R)-4-amino-3-(2-bromo-4-nitrophenoxy)pentan-2-yl]carbamate(350 mg, 0.77 mmol, 1.00 equiv), TEA (233 mg, 2.30 mmol, 3.00 equiv),4-dimethylaminopyridine (9.4 mg, 0.08 mmol, 0.10 equiv) and3,4-difluorobenzene-1-sulfonyl chloride (246 mg, 1.16 mmol, 1.50 equiv).The resulting mixture was stirred overnight at room temperature, thenconcentrated under vacuum. The crude product was applied onto a silicagel column with ethyl acetate/petroleum ether (1:20-100:1) to affordbenzylN-[(2S,3S,4R)-3-(2-bromo-4-nitrophenoxy)-4-[(3,4-difluorobenzene)sulfonamido]pentan-2-yl]carbamateas a yellow solid.

Step 7—Synthesis of benzyl((S)-1-((2S,3R)-4-((3,4-difluorophenyl)sulfonyl)-3-methyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl)carbamate

Into a 25-mL round-bottom flask was placed a solution of benzylN-[(2S,3S,4R)-3-(2-bromo-4-nitrophenoxy)-4-[(3,4-difluorobenzene)sulfonamido]pentan-2-yl]carbamate(320 mg, 0.51 mmol, 1.00 equiv) in MeCN (10 mL), CuI (10 mg, 0.051 mmol,0.1 equiv), potassium carbonate (140.8 mg, 1.02 mmol, 2.00 equiv) and1-N,2-N-dimethylcyclohexane-1,2-diamine (14 mg, 0.1 mmol, 0.2 equiv).The resulting solution was stirred overnight at 70° C., thenconcentrated under vacuum. The crude product was applied onto a silicagel column with ethyl acetate/petroleum ether (1:20-100:1) to affordbenzylN-[(1S)-1-[(2S,3R)-4-[(3,4-difluorobenzene)sulfonyl]-3-methyl-6-nitro-3,4-dihydro-2H-1,4-benzoxazin-2-yl]ethyl]carbamateas a yellow solid, which was used in the next step without furtherpurification.

Step 8—Synthesis of benzyl((S)-1-((2S,3R)-6-amino-4-((3,4-difluorophenyl)sulfonyl)-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl)carbamate

Into a 25-mL round-bottom flask was placed benzyl((S)-1-((2S,3R)-4-((3,4-difluorophenyl)sulfonyl)-3-methyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl)carbamate(110 mg, 0.19 mmol, 1.00 equiv), Raney-Ni (80 mg), methanol (5 mL) andhydrazine hydrate (0.2 mL). The resulting solution was stirred at roomtemperature for 20 min, then the solids were filtered out and thefiltrate concentrated under vacuum to afford the crude title compound asa yellow solid, which was used in the next step without furtherpurification.

Step 9—Synthesis of 1,1,1-trifluoro-2-methylpropan-2-ylN-[(2S,3R)-2-[(1S)-1-[[(benzyloxy)carbonyl]amino]ethyl]-4-[(3,4-difluorobenzene)sulfonyl]-3-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbamate

Into a 25-mL round-bottom flask was placed benzylN-[(1S)-1-[(2S,3R)-6-amino-4-[(3,4-difluorobenzene)sulfonyl]-3-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl]ethyl]carbamate(130 mg, 0.25 mmol, 1.00 equiv), TEA (25 mg, 0.25 mmol, 1.00 equiv) and1,1,1-trifluoro-2-methylpropan-(4-nitrophenyl) carbonate (60 mg, 0.25mmol, 1.0 eq.) in THF (5 mL). The resulting solution was stirred for 6days at 60° C., then concentrated under vacuum. The crude product waspurified by prep-HPLC (MeCN/water using TFA buffer) to afford1,1,1-trifluoro-2-methylpropan-2-ylN-[(2S,3R)-2-[(1S)-1-[[(benzyloxy)carbonyl]amino]ethyl]-4-[(3,4-difluorobenzene)sulfonyl]-3-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbamateas a white solid. ¹H-NMR (CD₃OD, 400 MHz) δ 8.02 (s, 1H), 7.77 (m, 1H),7.58 (m, 1H), 7.45-7.32 (m, 6H), 7.08 (m, 1H), 6.80 (m, 1H), 5.20 (m,2H), 4.68 (m, 1H), 3.65 (m, 1H), 3.27 (m, 1H), 1.79 (s, 6H), 1.26 (m,3H), 1.13 (m, 3H).

Example 87—Preparation of (R and S)-1,1,1-trifluoro-2-methylpropan-2-yl(3-(acetamidomethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(Example 87)

Step 1—Preparation of (R andS)-4-((4-fluorophenyl)sulfonyl)-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazine-3-carboxylicAcid

A mixture of (R and S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-3-(hydroxymethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(310 mg, 0.63 mmol), PhI(OAc)₂ (507 mg, 1.57 mmol) and TEMPO (196 mg,1.26 mmol) in CH₃CN/H₂O (5 mL/5 mL) was stirred at room temperatureovernight. The reaction was diluted with water, extracted with EtOAc andthe combined organic layers were washed with brine, dried over Na₂SO₄and concentrated. The crude product was purified by silica gel columnchromatography (DCM:MeOH=10:1) to afford the title product as a yellowoil. LCMS (ESI): calculated for C₂₀H₁₉F₄N₂O₇S [M+H]⁺: 507, found: 507;¹H NMR (400 MHz, CDCl₃) δ 7.80-7.84 (2H, m), 7.16 (2H, t, J=8.4 Hz),7.07 (1H, d, J=8.0 Hz), 6.77 (1H, d, J=8.4 Hz), 6.67 (1H, brs), 5.20(1H, brs), 4.63 (1H, d, J=10.0 Hz), 3.59 (3H, dd, J=11.2, 2.5 Hz), 1.75(6H, s).

Step 2—Preparation of (R and S)-1,1,1-trifluoro-2-methylpropan-2-yl(3-carbamoyl-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

A mixture of (R andS)-4-((4-fluorophenyl)sulfonyl)-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazine-3-carboxylicacid (15 mg, 0.03 mmol), HATU (14 mg, 0.036 mmol), NH₄Cl (2 mg, 0.036mmol) and DIPEA (11 mg, 0.09 mmol) in DMF (1 mL) was stirred at roomtemperature overnight. The reaction was diluted with water, extracted 3×with EtOAc and the combined extracts were washed with brine, dried overNa₂SO₄ and concentrated. The crude product was purified by prep-HPLC(petroleum ether:EtOAc=1.5:1) to afford the title product as a clearoil. LCMS (ESI): calculated for C₂₀H₂₀F₄N₃O₆S [M+H]⁺: 506, found: 506;¹H NMR (400 MHz, CDCl₃) δ 8.03 (1H, br s), 7.68 (2H, dd, J=8.8, 5.2 Hz),7.17 (3H, t, J=8.4 Hz), 6.80 (1H, d, J=9.2 Hz), 6.74 (1H, brs), 6.45(1H, brs), 5.55 (1H, brs), 4.89 (1H, brs), 4.71 (1H, dd, J=11.2, 1.6Hz), 3.10 (1H, dd, J=11.2, 3.2 Hz), 1.78 (6H, s).

Step 3—Preparation of (R and S)-1,1,1-trifluoro-2-methylpropan-2-yl(3-(aminomethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (R and S)-1,1,1-trifluoro-2-methylpropan-2-yl(3-carbamoyl-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(50 mg, 0.10 mmol) in THF (5 mL) was added dropwise BH₃.SMe₂(75 mg, 0.99mmol) at 0° C. The reaction mixture was stirred at 75° C. for 48 h underN₂ atmosphere. Upon completion, the reaction was diluted with water,extracted 3× with EtOAc and the combined organic layers were washed withbrine, dried over Na₂SO₄ and concentrated. The crude product waspurified by prep-TLC (petroleum ether:EtOAc=1.5:1) to afford the titleproduct as a clear oil. LCMS (ESI): calculated for C₂₀H₂₂F₄N₃O₅S [M+H]⁺:492, found: 492; ¹H NMR (400 MHz, CDCl₃) δ 7.79 (1H, d, J=2.4 Hz), 7.60(2H, dd, J=8.8, 4.8 Hz, 2H), 7.38 (1H, brs), 7.33 (1H, d, J=7.6 Hz),7.10 (2H, t, J=8.4 Hz), 6.68 (1H, d, J=9.2 Hz, 1H), 4.66 (1H, d, J=8.4Hz), 4.05 (1H, d, J=11.6 Hz), 2.92-3.16 (3H, m), 1.73 (6H, d, J=3.2 Hz).

Step 4—Preparation of (R and S)-1,1,1-trifluoro-2-methylpropan-2-yl(3-(acetamidomethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

A mixture of (R andS)-1,1,1-trifluoro-2-methylpropan-2-yl(3-(aminomethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (10 mg, 0.02mmol), Et₃N (21 mg, 0.20 mmol) and AcCl (8 mg, 0.10 mmol) in DCM (3 mL)was stirred at 0° C. for 1 h. The reaction was then diluted with waterand extracted 3× with EtOAc. The organic layers were washed with brine,dried over Na₂SO₄ and concentrated. The crude product was purified byprep-TLC (petroleum ether:EtOAc=1:1) to afford the title product as ayellow solid. LCMS (ESI): calculated for C₂₂H₂₄F₄N₃O₆S [M+H]⁺: 534,found: 534; ¹H NMR (400 MHz, CDCl₃) δ 7.94 (1H, brs), 7.66 (2H, dd,J=8.8, 5.2 Hz), 7.08-7.22 (3H, m), 6.78 (1H, d, J=9.2 Hz), 6.70 (1H,brs), 5.93 (1H, brs), 4.43 (1H, d, J=10.0 Hz), 3.99 (1H, d, J=11.2 Hz),3.58 (1H, dd, J=14.0, 7.2 Hz), 3.12 (1H, dd, J=11.6, 3.2 Hz), 2.95 (1H,ddd, J=14.4, 10.0, 4.4 Hz), 2.05 (3H, s), 1.78 (6H, s).

Example 88—Preparation of(R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-((1-carbamoylcyclopropyl)methyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamateand(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-((1-carbamoylcyclopropyl)methyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(Examples 88A and 88B) Step 1—Preparation of(R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-((1-carbamoylcyclopropyl)methyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (R or S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-((1-cyanocyclopropyl)methyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(Isomer 1 from Example 93, Step 5, 150 mg, 0.279 mmol) in DMSO (2 mL)was added K₂CO₃ (77 mg, 0.558 mmol) and 30% H₂O₂ (0.049 ml, 0.558 mmol)at 25° C. under nitrogen. The reaction mixture was stirred at 25° C. for18 h, then diluted with ethyl acetate (40 mL) and washed with brine (15mL×3). The combined organic layers were dried over Na₂SO₄ and evaporatedto afford the title compound (Isomer 1 from Step 1) as yellow oil.

The other enantiomer (Isomer 2 from Step 1) was prepared using a similarprocedure. Both enantiomers have the same analytical data: LCMS (ESI)calculated for C₂₅H₂₉F₃N₃O₆S [M+H]⁺: 556.1, found: 556.2.

Step 2—Preparation of(R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-((1-carbamoylcyclopropyl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamateand(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-((1-carbamoylcyclopropyl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (R orS)-1,1,1-trifluoro-2-methylpropan-2-yl(2-((1-carbamoylcyclopropyl)methyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(Isomer 1 from Step 1, 150 mg, 0.270 mmol)) in MeOH (15 mL) was addedmagnesium (131 mg, 5.40 mmol) in one portion at 25° C. under nitrogen.The reaction was stirred at 25° C. for 18 hours, then quenched withsaturated NH₄Cl solution (60 mL) and extracted with EtOAc (3×50 mL). Theorganic layers were combined, dried over Na₂SO₄, filtered and thefiltrate concentrated in vacuo. The crude product was purified byprep-TLC (petroleum ether:EtOAc=1:2) to afford the title compound(Isomer 1 from Step 2) as a colorless oil.

The other enantiomer (Isomer 2 from Step 2) was prepared using a similarprocedure from Isomer 2 from Step 1. Both enantiomers have the sameanalytical data: LCMS (ESI) calculated for C₁₈H₂₃F₃N₃O₄ [M+H]⁺: 402.1,found: 402.3.

Step 3—Preparation of(R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-((1-carbamoylcyclopropyl)methyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamateand(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-((1-carbamoylcyclopropyl)methyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (R orS)-1,1,1-trifluoro-2-methylpropan-2-yl(2-((1-carbamoylcyclopropyl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(Isomer 1 from Step 2, 40 mg, 0.100 mmol) in pyridine (2 mL) and THF (2mL) was added 3-chloro-1-ethyl-1H-pyrazole-4-sulfonyl chloride (45.7 mg,0.199 mmol). The reaction was stirred at 25° C. for 18 h, thenconcentrated. The title compound (Isomer 1 from Step 3, Example 88A) wasobtained by pre-HPLC (MeCN/water using TFA buffer) as a white solid.

The other enantiomer (Isomer 2 from Step 3, Example 88B) was preparedusing a similar procedure from Isomer 2 from Step 2. Both enantiomershave the same analytical data: LCMS (ESI) calculated for C₂₃H₂₈ClF₃N₅O₆S[M+H]⁺: 594.1, found: 594.1; ¹H-NMR (CDCl₃, 400 MHz) δ 8.10 (1H, s),7.86 (1H, s), 6.84-6.86 (1H, m), 6.74-6.77 (2H, m), 4.36 (1H, d, J=12.0Hz), 4.05-4.11 (3H, m,), 3.34-3.40 (1H, m), 2.07-2.13 (2H, m), 1.73 (6H,s), 1.43-1.47 (3H, m), 1.23-1.29 (2H, m), 0.77-0.82 (2H, m).

Example 89—Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl((S)-2-((R)-3-amino-2-cyclopropyl-3-oxopropyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamateand 1,1,1-trifluoro-2-methylpropan-2-yl((S)-2-((S)-3-amino-2-cyclopropyl-3-oxopropyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(Examples 89A and 89B)

Step 1—Preparation of (S)-methyl2-(4-benzyl-6-((tert-butoxycarbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate

To a solution of (S)-methyl2-(6-((tert-butoxycarbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate(1.3 g, 4.03 mmol) in dimethyl formamide (7 mL) were added potassiumcarbonate (0.836 g, 6.05 mmol) and (bromomethyl)benzene (1.035 g, 6.05mmol). The resulting mixture was stirred at 20° C. for 18 h, thendiluted with water (150 mL) and extracted with ethyl acetate (3×100 mL).The separated organic layers were washed with brine, dried with Na₂SO₄and concentrated under reduced pressure to give the crude product whichwas purified by flash column chromatography (petroleum ether:ethylacetate=10:1 to 5:1) to give the title compound as a white solid. LCMS(ESI) calculated for C₂₃H₂₉N₂O₅ [M+H]⁺: 413, found: 413. ¹H NMR (400MHz, CDCl3) 7.28-7.38 (5H, m), 6.78 (1H, br s), 6.72 (1H, d, J=8.61 Hz),6.59 (1H, d, J=7.43 Hz), 6.24 (1H, brs), 4.54-4.60 (1H, m), 4.37-4.49(2H, m), 3.69 (3H, s), 3.33 (1H, dd, J=1.96, 11.74 Hz), 3.12 (1H, dd,J=6.85, 11.54 Hz), 2.76 (1H, dd, J=6.85, 15.85 Hz), 2.57 (1H, dd,J=6.26, 16.04 Hz), 1.46 (9H, s).

Step 2—Preparation of(S)-2-(4-benzyl-6-((tert-butoxycarbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)aceticAcid

To a solution of (S)-methyl2-(4-benzyl-6-((tert-butoxycarbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate(2.6 g, 6.30 mmol) in dioxane (26 mL) and water (26 ml) was addedlithium hydroxide (0.226 g, 9.46 mmol), and the resulting mixture wasstirred at 20° C. for 18 h. The reaction was diluted with water (100mL), extracted with ethyl acetate (50 mL×3) and the aqueous layer wasacidified with hydrochloric acid (1M, 10 mL) to pH=3. The mixture wasextracted with ethyl acetate (100 mL) and the combined organic layerswere dried (Na₂SO₄), filtered and concentrated under reduced pressure togive the crude title compound as a yellow solid, which was used in nextstep without further purification. LCMS (ESI) calculated for C₂₂H₂₇N₂O₅[M+H]⁺: 399, found: 399. ¹H NMR (400 MHz, Methanol-d4) 7.31-7.35 (5H,m), 7.23-7.26 (1H, m), 6.88 (1H, br s), 6.62-6.65 (1H, m), 6.55-6.60(1H, m), 4.43-4.50 (3H, m), 3.35-3.39 (1H, m), 3.11 (1H, dd, J=7.28,11.80 Hz), 2.62 (2H, t, J=6.27 Hz), 1.46 (9H, s).

Step 3—Preparation of (S)-tert-butyl(4-benzyl-2-(2-(methoxy(methyl)amino)-2-oxoethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of(S)-2-(4-benzyl-6-((tert-butoxycarbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)aceticacid (2 g, 5.02 mmol) in dichloromethane (20 mL) were addedtriethylamine (3.50 ml, 25.10 mmol) and HATU (2.290 g, 6.02 mmol), andthe resulting mixture was stirred at 20° C. for 30 min, followed by theaddition of N,O-dimethylhydroxylamine (1.533 g, 25.10 mmol). Thereaction was stirred at 20° C. for 5 minutes, then concentrated underreduced pressure to give the crude product. Flash column chromatographypurification (petroleum ether:ethyl acetate=3:1 to 1:1) afforded thetitle compound as a yellow oil. LCMS (ESI) calculated for C₂₄H₃₂N₃O₅[M+H]⁺: 442, found: 442. ¹H NMR (400 MHz, CDCl₃) 7.25-7.33 (5H, m), 6.70(2H, d, J=8.61 Hz), 6.60 (1H, d, J=7.83 Hz), 6.24 (1H, brs), 4.64 (1H,dd, J=1.76, 6.46 Hz), 4.37-4.51 (2H, m), 3.67 (3H, s), 3.41 (1H, dd,J=1.96, 11.74 Hz), 3.21-3.24 (2H, m), 3.01 (3H, s), 2.61 (1H, dd,J=6.46, 15.85 Hz), 1.46 (9H, s), 1.36 (5H, t, J=7.24 Hz).

Step 4—Preparation of (S)-tert-butyl(4-benzyl-2-(2-cyclopropyl-2-oxoethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (S)-tert-butyl(4-benzyl-2-(2-(methoxy(methyl)amino)-2-oxoethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(6 g, 13.59 mmol) in THF (30 mL) was added dropwise cyclopropylmagnesiumbromide (272 ml, 136 mmol) at 0° C. under N₂. The reaction was stirredfor 4 h at 0° C., then quenched with sat. NH₄Cl aqueous (50 mL). Thebiphasic mixture was extracted with EtOAc (50 mL×3), dried over Na₂SO₄and concentrated to afford the crude title compound as a yellow solid,which was used in next step without further purification. LCMS (ESI)calculated for C₂₅H₃₁N₂O₄ [M+H]⁺: 423, found: 423. ¹HNMR (400 MHz,CDCl₃) δ 7.28-7.34 (5H, m), 6.76 (1H, br s), 6.71 (1H, d, J=8.8 Hz),6.60 (1H, d, J=6.8 Hz), 6.21 (1H, br s), 4.62 (1H, d, J=0.8 Hz), 4.43(2H, q, J=8.0 Hz), 3.33-3.36 (1H, m), 3.01-3.13 (2H, m), 2.77-2.79 (1H,m), 1.93-1.96 (1H, m), 1.47 (9H, s), 1.03-1.06 (2H, m), 0.88-0.90 (2H,m).

Step 5—Preparation of tert-butyl ((S)-4-benzyl-2-((S andR)-2-cyano-2-cyclopropylethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (S)-tert-butyl(4-benzyl-2-(2-cyclopropyl-2-oxoethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(4.5 g, 10.65 mmol) and 1-((isocyanomethyl)sulfonyl)-4-methylbenzene(4.16 g, 21.30 mmol) in DME (150 mL) and ethanol (5 mL) was added NaOH(1.278 g, 32.0 mmol) in portions under N₂ at 0° C. The reaction wasstirred at 30° C. for 18 h, then diluted with DCM (100 mL), washed withwater (60 mL×2) and brine and dried over Na₂SO₄. After concentration,the crude product was purified by silica gel column chromatography(petroleum ether:EtOAc=6:1) to afford the title compound as a yellowoil. LCMS (ESI) calculated for C₂₆H₃₂N₃O₃ [M+H]⁺: 434, found: 434. ¹HNMR(400 MHz, CDCl₃) δ 7.29-7.36 (5H, m), 6.81 (1H, d, J=7.2 Hz), 6.72 (1H,d, J=7.2 Hz), 6.60 (1H, d, J=7.2 Hz), 6.23 (1H, br s), 4.42-4.45 (2H,m), 4.33-4.38 (1H, m), 3.24-3.29 (1H, m), 3.08-3.13 (2H, m), 2.55-2.65(1H, m), 2.41-2.47 (1H, m), 1.85-2.05 (3H, m), 1.47 (9H, s), 0.63-0.66(2H, m), 0.41-0.45 (2H, m).

Step 6—Preparation of (R andS)-3-((S)-6-amino-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-cyclopropylpropanamide

To MeOH (10 mL) at 0° C. was added slowly sulfurous dichloride (3 mL,2.076 mmol) and the mixture was stirred at 0° C. for 30 mins, followedby the addition of tert-butyl ((S)-4-benzyl-2-((S andR)-2-cyano-2-cyclopropylethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(900 mg, 2.076 mmol). The reaction was stirred at 70° C. for 18 h, thenquenched with 5 mL of water. The resulting mixture was adjusted topH=7˜8 with saturated solution of NaHCO₃, extracted with EtOAc (15 mL×3)and dried over Na₂SO₄. Purification by chromatography column (petroleumether/EtOAc=10:1 to 1:2) afforded the title compound all as black oil.LCMS (ESI) calculated for C₂₁H₂₆N₃O₂ [M+H]⁺: 352, found: 352.

Step 7—Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl ((S)-2-((S andR)-3-amino-2-cyclopropyl-3-oxopropyl)-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (R andS)-3-((S)-6-amino-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-cyclopropylpropanamide(280 mg, 0.797 mmol) in DMSO (8 mL) was added1-(((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)-1H-imidazol-3-iumiodide (307 mg, 0.876 mmol), then the reaction was stirred at 20° C. for1 h. The reaction mixture was extracted with EtOAc and water, washedwith brine and dried over Na₂SO₄. The crude product was purified byprep-TLC (petroleum ether/EtOAc=1:1) to afford the title compound as ared oil. LCMS (ESI) calculated for C₂₆H₃₁F₃N₃O₄ [M+H]⁺: 506.2, found:506.2. ¹H-NMR (CDCl₃, 400 MHz) δ 7.07-7.18 (5H, m), 6.48-6.52 (2H, m),6.36 (1H, s), 5.53 (2H, d, J=10.8 Hz), 3.92-4.00 (2H, m), 3.06-3.09 (1H,m), 2.92-2.96 (1H, m), 1.62-1.73 (2H, m), 1.54 (6H, s), 0.81-0.83 (1H,m), 0.41 (2H, d, J=8.0 Hz), 0.12-0.16 (1H, m), 0.00-0.02 (1H, m).

Step 8—Preparation of1,1,1-trifluoro-2-methylpropan-2-yl((S)-2-((S)-3-amino-2-cyclopropyl-3-oxopropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamateand1,1,1-trifluoro-2-methylpropan-2-yl((S)-2-((R)-3-amino-2-cyclopropyl-3-oxopropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of 1,1,1-trifluoro-2-methylpropan-2-yl ((S)-2-((S andR)-3-amino-2-cyclopropyl-3-oxopropyl)-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(100 mg, 0.198 mmol) in EtOAc (10 mL) was added Pd/C (10 mg, 10%). Thereaction was stirred under balloon of hydrogen at 20° C. for 8 hours,then filtered and concentrated. Purification by prep-TLC (petroleumether/EtOAc=1:1) afforded the title mixture of diastereomers as a lightyellow oil. LCMS (ESI) calculated for C₁₉H₂₅F₃N₃O₄ [M+H]⁺: 416.1, found:416.1.

The above mixture was resolved by SFC method (SFC-80 Column: ChiralpakAD, 10 μm, Daicel Chemical Industries, Ltd 250×30 mm I.D., Mobile phase:A: Supercritical CO₂, B: EtOH (25%) (contained 75% NH₃.H₂O) Flow rate:60 mL/min, Wavelength: 220 nm) to yield two isomers: faster eluent(Isomer 1 from Step 8) and slower eluent (Isomer 2 from Step 8).

Step 9—Preparation of1,1,1-trifluoro-2-methylpropan-2-yl((S)-2-((R)-3-amino-2-cyclopropyl-3-oxopropyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamateand 1,1,1-trifluoro-2-methylpropan-2-yl((S)-2-((S)-3-amino-2-cyclopropyl-3-oxopropyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of 1,1,1-trifluoro-2-methylpropan-2-yl((S)-2-((S orR)-3-amino-2-cyclopropyl-3-oxopropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(Isomer 1 from Step 8, 6 mg, 0.014 mmol) in THF (1 mL) were addedpyridine (1 mL) and 3-chloro-1-ethyl-1H-pyrazole-4-sulfonyl chloride(19.85 mg, 0.087 mmol) at room temperature under N₂. The reaction wasstirred at 20° C. for 18 h, then concentrated. Purification by prep-HPLC(MeCN/water using TFA buffer) afforded the title compound (Isomer 1,Example 89A) as a white solid. LCMS (ESI) calculated for C₂₄H₃₀ClF₃N₅O₆S[M+H]⁺: 608.1, found: 608.1; ¹H-NMR (CDCl₃, 400 MHz) δ 8.10 (1H, s),7.84 (1H, s), 6.89 (1H, d, J=7.2 Hz), 6.76 (1H, d, J=9.2 Hz), 6.01 (1H,s), 5.81 (1H, s), 4.31 (1H, d, J=14.4 Hz), 4.12 (2H, q, J=7.2 Hz), 4.02(1H, s), 3.36 (1H, t, J=12.8 Hz), 2.05-2.15 (3H, m), 1.76 (6H, s), 1.49(1H, t, J=7.2 Hz), 1.00 (1H, s), 0.66 (2H, d, J=7.6 Hz), 0.32-0.35 (1H,m), 0.22-0.24 (1H, m).

The other isomer (Isomer 2, Example 89B) was prepared using a similarprocedure from Isomer 2 from Step 8. LCMS (ESI) calculated forC₂₄H₃₀ClF₃N₅O₆S [M+H]⁺: 608.1, found: 608.1; ¹H-NMR (CDCl₃, 400 MHz) δ8.10 (1H, s), 7.84 (1H, s), 6.89 (1H, d, J=7.2 Hz), 6.76 (1H, d, J=8.8Hz), 6.59 (1H, s), 6.14 (1H, s), 5.84 (1H, s), 4.32 (1H, d, J=13.6 Hz),4.12 (2H, q, J=7.2 Hz), 4.03 (1H, s), 3.37 (1H, t, J=12.0 Hz), 1.85-1.96(2H, m), 1.76 (6H, s), 1.49 (1H, t, J=7.2 Hz), 1.00 (1H, s), 0.66 (2H,d, J=7.2 Hz), 0.33-0.37 (1H, m), 0.22-0.24 (1H, m).

Example 90—Preparation of(R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(3-amino-2,2-dimethyl-3-oxopropyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamateand(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(3-amino-2,2-dimethyl-3-oxopropyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(Examples 90A and 90B)

To a solution of (R orS)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-cyano-2-methylpropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(see Isomer 1 in Example 94; 40 mg, 0.069 mmol) in DMSO (0.5 ml) wereadded K₂CO₃ (28.7 mg, 0.208 mmol) and 30% H₂O₂ (0.141 ml, 1.384 mmol)dropwise at 0° C. under nitrogen. After 1 h, another batch of 30% H₂O₂(0.141 ml, 1.384 mmol) was added. The reaction was stirred at roomtemperature for 6 h, then quenched with Na₂SO₃, filtered andconcentrated. The crude product was purified by prep-HPLC (MeCN/waterusing TFA buffer) to afford the title product (Isomer 1, Example 90A) asa white solid.

The other enantiomer (Isomer 2, Example 90B)) was prepared using asimilar procedure from Isomer 2 in Example 94. Both enantiomers have thesame analytical data: LCMS (ESI) calculated for C₂₃H₃₀ClF₃N₅O₆S [M+H]⁺:596, found: 596. ¹H-NMR (CDCl₃, 400 MHz) δ 8.13 (brs, 1H), 7.86 (br s,1H), 7.16 (br s, 1H), 6.76 (d, J=7.8 Hz, 1H), 6.65-6.72 (m, 1H), 6.60(br s, 1H), 6.04 (br s, 1H), 4.23 (d, J=13.3 Hz, 1H), 4.08 (q, J=7.0 Hz,3H), 3.40 (dd, J=8.6, 13.3 Hz, 1H), 2.00 (dd, J=9.3, 14.4 Hz, 1H), 1.78(d, J=14.8 Hz, 1H), 1.73 (s, 6H), 1.45 (t, J=7.2 Hz, 3H), 1.30 (s, 6H).

Example 91—Preparation of Additional Amides from Propionic Acids

The compounds in Table 27 below were prepared based on the experimentalprocedures described in Examples 89 and 90 and elsewhere in the detaileddescription, and can be achieved by one of skill in the art in light ofthe present disclosure.

TABLE 27 Ex. Observed No. Structure Name m/z 91A

(R)-1,1,1-trifluoro-2- methylpropan-2-yl (2-(3- amino-2,2-dimethyl-3-oxopropyl)-4-((3-chloro-1- ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 596(M + H)+ 91B

(S)-1,1,1-trifluoro-2- methylpropan-2-yl (2-(3- amino-2,2-dimethyl-3-oxopropyl)-4-((3-chloro-1- ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 596(M + H)+ 91C

2,2,2-trifluoro-1,1- dimethylethyl {(2S)-2-(3- amino-2,2-dimethyl-3-oxopropyl)-4-[(4-fluoro-3- methoxyphenyl)sulfonyl]- 3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbamate 592 (M + H)+ 91D

1,1,1-trifluoro-2- methylpropan-2-yl ((S)-2- ((S or R)-3-amino-2-cyclopropyl-3-oxopropyl)- 4-((4-fluoro-3- methoxyphenyl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 626 (M + Na)+ 91E

1,1,1-trifluoro-2- methylpropan-2-yl ((S)-2- ((S or R)-3-amino-2-cyclopropyl-3-oxopropyl)- 4-((3-ethoxy-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4- dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 618 (M + H)+ 91F

1,1,1-trifluoro-2- methylpropan-2-yl ((S)-2- ((S or R)-3-amino-2-cyclopropyl-3-oxopropyl)- 4-((4-fluoro-3- methoxyphenyl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 604 (M + H)+ 91G

1,1,1-trifluoro-2- methylpropan-2-yl ((S)-2- ((S or R)-3-amino-2-cyclopropyl-3-oxopropyl)-4- ((3-ethoxy-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4- dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 618 (M + H)+ 91H

2,2,2-trifluoro-1,1- dimethylethyl [(2S)-2-(3- amino-2,2-dimethyl-3-oxopropyl)-4-{[5- (trifluoromethyl)pyridin-3- yl]sulfonyl}-3,4-dihydro-2H-1,4-benzoxazin-6- yl]carbamate 613 (M + H)+ 91i

2,2,2-trifluoro-1,1- dimethylethyl {2-(3-amino-2,2-dimethyl-3-oxopropyl)- 4-[(3-ethoxy-1-ethyl-1H-pyrazol-4-yl)sulfonyl]-3,4- dihydro-2H-1,4-benzoxazin- 6-yl}carbamate606 (M + H)+ 91J

2,2,2-trifluoro-1,1- dimethylethyl [2-(3-amino-2,2-dimethyl-3-oxopropyl)- 4-{[1-ethyl-3-(2- hydroxyethoxy)-1H-pyrazol-4-yl]sulfonyl}-3,4-dihydro- 2H-1,4-benzoxazin-6- yl]carbamate 622 (M +H)+ 91K

(S)-methyl 2-((4-((2-(3- amino-2,2-dimethyl-3- oxopropyl)-6-((((1,1,1-trifluoro-2-methylpropan-2- yl)oxy)carbonyl)amino)-2H-benzo[b][1,4]oxazin-4(3H)- yl)sulfonyl)-1-ethyl-1H-pyrazol-3-yl)oxy)acetate 650 (M + H)+

Example 92—Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-cyanoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamateExample 92

Step 1—Preparation of(R)-4-benzyl-2-(bromomethyl)-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine

To(R)-(4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methanol(10 g, 33.3 mmol) and perbromomethane (16.56 g, 49.9 mmol) in THF (100mL) was added triphenylphosphine (21.83 g, 83 mmol) portionwise and thereaction stirred at 30° C. for 2 h. The reaction was cooled, water (50mL) was added and the resulting biphasic mixture was extracted withethyl acetate (100 mL). The combined organic layers were washed withbrine (30 mL), dried over Na₂SO₄, filtered and the filtrate evaporatedunder reduced pressure. The crude product was purified by columnchromatography on silica gel, eluting with (petroleum ether:EtOAc=10:1)to give(R)-4-benzyl-2-(bromomethyl)-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazineas a yellow solid. LCMS (ESI) calculated for C₁₆H₁₆BrN₂O₃ [M+H]⁺:363/365, found: 363/365. ¹H NMR (CDCl₃, 400 MHz) δ 7.51-7.60 (m, 2H),7.20-7.35 (m, 6H), 6.83 (d, J=8.6 Hz, 1H), 4.45 (d, J=4.7 Hz, 2H),3.27-3.53 (m, 5H).

Step 2—Preparation of (R and S)-methyl3-((S)-4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-cyanopropanoate

(R)-4-benzyl-2-(bromomethyl)-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine(250 mg, 0.6 mmol), methyl 2-cyanoacetate (682 mg, 6.8 mmol) and K₂CO₃(171 mg, 1.239 mmol) in DMSO (2.5 ml) were stirred at 90° C. for 0.5 h.Upon completion, the reaction solution was filtrated and the filtratewas used in the next step with no further purification. LCMS (ESI)calculated for C₂₀H₂₀N₃O₅ [M+H]⁺: 382 found: 382.

Step 3—Preparation of methyl(S)-3-(4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanenitrile

To a flask with (R and S)-methyl3-((S)-4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-cyanopropanoate(250 mg, 0.6 mmol) was added lithium chloride (139 mg, 3.3 mmol) in DMSO(2.5 mL) and the reaction was stirred at 160° C. for 0.5 h. The reactionsolution was cooled, water (10 mL) was added and the resulting biphasicmixture was extracted with ethyl acetate (25 mL). The combined organiclayers were washed with aqueous ammonium chloride (10 mL), dried(Na₂SO₄), filtered and the solvent was evaporated under reducedpressure. The crude product was purified by prep-TLC eluting with(petroleum ether:EtOAc=5:1 to 3:1) to afford the title compound as ayellow oil. LCMS (ESI) calculated for C₁₈H₁₈N₃O₃ [M+H]⁺: 324, found:324. ¹H NMR (CDCl₃, 400 MHz,) δ 7.48-7.59 (m, 2H), 7.20-7.36 (m, 5H),6.81 (d, J=8.6 Hz, 1H), 4.44 (s, 2H), 4.29 (t, J=8.0 Hz, 1H), 3.28 (dd,J=2.1, 11.9 Hz, 1H), 3.09 (dd, J=7.4, 11.7 Hz, 1H), 2.47-2.65 (m, 2H),1.85-1.95 (m, 2H).

Step 4—Preparation of(S)-3-(6-amino-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanenitrile

Methyl(S)-3-(4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanenitrile(1.6 g, 4.9 mmol) and Pd/C (1.7 g, 10%) in EtOH (30 ml) were stirredunder H₂ at 1 atm at 25° C. for 4 h. Upon completion, the reactionmixture was filtrated and the filtrate concentrated. The crude product(S)-3-(6-amino-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanenitrilewas used in next step without further purification. LCMS (ESI)calculated for C₁₁H₁₄N₃O [M+H]+: 204, found: 204. ¹H NMR (CDCl₃, 400MHz) δ 6.53 (d, J=8.2 Hz, 1H), 5.87-6.04 (m, 2H), 4.07 (t, J=8.2 Hz,1H), 3.31 (dd, J=2.1, 11.1 Hz, 1H), 3.03-3.14 (m, 1H), 2.53 (t, J=7.2Hz, 2H), 1.82-2.00 (m, 2H).

Step 5—Preparation of(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-cyanoethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

(S)-3-(6-amino-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanenitrile(1.0 g, 4.9 mmol) and3-methyl-1-(((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)-1H-imidazol-3-iumiodide (1.971 g, 5.41 mmol) were stirred at 28° C. in DMSO (20 mL) for10 h, then treated with water (150 mL) and extracted with ethyl acetate(3×100 mL). The combined organic fractions were washed with aqueousammonium chloride (20 mL), dried (Na₂SO₄), filtered and the filtrateevaporated under reduced pressure. The crude product was purified bycolumn chromatography on silica gel (petroleum ether:EtOAc=3:1) to givethe title product as a brown oil. LCMS (ESI) calculated for C₁₆H₁₉F₃N₃O₃[M+H]⁺: 358, found: 358. ¹H NMR (CDCl₃, 400 MHz) δ 6.83 (br s, 1H), 6.65(d, J=8.6 Hz, 1H), 6.42 (d, J=6.2 Hz, 2H), 4.14 (br s, 1H), 3.36 (d,J=11.3 Hz, 1H), 3.10 (dd, J=7.2, 11.5 Hz, 1H), 2.55 (t, J=7.0 Hz, 2H),1.82-1.97 (m, 2H), 1.67 (s, 6H).

Step 6—Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-cyanoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-cyanoethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(250 mg, 0.7 mmol) and pyridine (332 mg, 4.2 mmol) in DCM (6 mL) wastreated with 3-(trifluoromethyl)benzene-1-sulfonyl chloride (513 mg,2.10 mmol) and the resulting mixture was stirred at 30° C. for 8 h. Thereaction was cooled to room temperature, then treated with water (5 mL).The resulting biphasic mixture was extracted with dichloromethane (3×5mL). The combined organic layers were washed with aqueous ammoniumchloride (5 mL), dried (Na₂SO₄), filtered and the filtrate wasevaporated under reduced pressure. The crude product was purified byprep-TLC (petroleum ether:EtOAc=3:1) to give the title compound as awhite solid. LCMS (ESI) calculated for C₂₃H₂₂F₆N₃O₅S [M+H]⁺: 566, found:566. ¹H NMR (CDCl₃, 400 MHz) δ 7.99 (br s, 1H), 7.74-7.91 (m, 3H),7.53-7.68 (m, 1H), 6.99 (dd, J=2.1, 8.8 Hz, 1H), 6.72 (d, J=8.6 Hz, 1H),6.54 (brs, 1H), 4.20 (d, J=14.0 Hz, 1H), 3.57 (brs, 1H), 3.23 (dd,J=9.3, 14.0 Hz, 1H), 2.47 (t, J=6.8 Hz, 2H), 1.75-1.89 (m, 2H), 1.70 (s,6H).

Example 93—Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-((1-cyanocyclopropyl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamateand (R)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-((1-cyanocyclopropyl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(Examples 93A and 93B)

Step 1—Preparation of 1-allylcyclopropanecarbonitrile

To a solution of cyclopropanecarbonitrile (10 g, 149 mmol) in THF (10mL) was added LDA (82 ml, 164 mmol) dropwise at 0° C. under nitrogen.After 10 min, the mixture was added dropwise to the solution of3-bromoprop-1-ene (18.93 g, 157 mmol) in THF (20 mL) at 0° C. Thereaction was stirred at 0° C. for 1 h, then quenched with saturatedNH₄Cl solution (20 mL) and diluted with water (200 mL). The organiclayer was separated and the resulting aqueous solution extracted withDCM (35 mL×3). The combined organic layers were washed with brine, driedover Na₂SO₄ and evaporated to dryness at low temperature (<30° C.). Thecrude product was purified by silica gel chromatography eluted with purepetroleum ether to afford the title compound as a yellow oil. ¹H-NMR(CD₃OD, 400 MHz) δ 5.83 (tdd, J=6.9, 10.0, 16.8 Hz, 1H), 5.11-5.24 (m,2H), 2.20 (brs, 2H), 1.18-1.26 (m, 2H), 0.79-0.85 (m, 2H).

Step 2—Preparation of (R andS)-1-(oxiran-2-ylmethyl)cyclopropanecarbonitrile

To a solution of 1-allylcyclopropanecarbonitrile (8 g, 74.7 mmol) in DCM(80 ml) was added m-CPBA (18.19 g, 90 mmol) in portions at 0° C. Thereaction was stirred at 25° C. for 30 h, then diluted with DCM (100 mL).The organic layer was washed with 1M NaOH solution (60 mL×3) and brine(60 mL×2), dried over Na₂SO₄ and evaporated to afford the crude titleproduct as a yellow oil, which was used directly in the next stepwithout further purification. ¹H-NMR (CD₃OD, 400 MHz) δ 3.11 (d, J=1.9Hz, 1H), 2.82 (t, J=4.1 Hz, 1H), 2.56 (dd, J=2.5, 4.1 Hz, 1H), 1.89 (dd,J=5.0, 14.4 Hz, 1H), 1.42-1.54 (m, 1H), 1.20-1.31 (m, 2H), 0.90-0.99 (m,1H), 0.82-0.88 (m, 1H).

Step 3—Preparation of (R andS)-1-((6-nitro-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl)cyclopropanecarbonitrile

To a solution of N-(2-fluoro-5-nitrophenyl)-4-methylbenzenesulfonamide(1 g, 3.23 mmol) in DMF (10 mL) were added (R andS)-1-(oxiran-2-ylmethyl)cyclopropanecarbonitrile (1 g, 8.13 mmol),N-benzyl-N,N-diethylethanaminium chloride (0.110 g, 0.48 mmol) andpotassium carbonate (1.56 g, 11.27 mmol) in one portion at roomtemperature under nitrogen. The reaction was stirred at 100° C. in amicrowave for 2 h. Another two batches were run on the same scale asdescribed above and all three mixtures were cooled to room temperature,combined, diluted with water (400 mL) and extracted with EtOAc (100mL×4). The combined organic layers were washed with brine, dried overNa₂SO₄ and evaporated to dryness. The crude product was purified bysilica column (petroleum ether:EtOAc=5:1 to 3:1) to afford the titleproduct as a yellow solid. LCMS (ESI) calculated for C₂₀H₂₀N₃O₅S [M+H]⁺:414, found: 414. ¹H-NMR (CDCl₃, 400 MHz) δ 8.75 (br s, 1H), 7.87-8.00(m, 1H), 7.61 (d, J=8.2 Hz, 2H), 7.31 (d, J=7.8 Hz, 2H), 6.93 (d, J=9.0Hz, 1H), 4.32 (d, J=14.4 Hz, 1H), 3.82 (br s, 1H), 3.26 (dd, J=9.3, 14.0Hz, 1H), 2.40 (s, 3H), 1.64-1.81 (m, 2H), 1.32 (brs, 2H), 0.89-0.97 (m,1H), 0.78-0.85 (m, 1H).

Step 4—Preparation of (R andS)-1-((6-amino-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl)cyclopropanecarbonitrile

To a solution of (R andS)-1-((6-nitro-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl)cyclopropanecarbonitrile(1.5 g, 3.63 mmol) in EtOAc (30 mL) was added Pd/C (0.6 g, 5.64 mmol) inone portion at room temperature. The reaction was stirred at 25° C.under a H₂ balloon for 8 h, then filtered and evaporated to dryness. Thecrude title product was used directly in the next step without furtherpurification. LCMS (ESI) calculated for C₂₀H₂₂N₃O₃S [M+H]⁺: 384, found:384. ¹H-NMR (CDCl₃, 400 MHz) δ 7.55 (d, J=8.2 Hz, 2H), 7.25 (d, J=7.0Hz, 3H), 6.62 (d, J=8.6 Hz, 1H), 6.44 (dd, J=2.5, 8.4 Hz, 1H), 4.25 (dd,J=1.7, 14.2 Hz, 1H), 3.45-3.56 (m, 1H), 3.14 (dd, J=9.5, 14.2 Hz, 1H),2.37 (s, 3H), 1.59-1.67 (m, 1H), 1.50-1.59 (m, 1H), 1.20-1.29 (m, 2H),0.86-0.94 (m, 1H), 0.69-0.79 (m, 1H).

Step 5—Preparation of(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-((1-cyanocyclopropyl)methyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamateand(R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-((1-cyanocyclopropyl)methyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (R andS)-1-((6-amino-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl)cyclopropanecarbonitrile(1.3 g, 3.39 mmol) in DMSO (15 ml) was added1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate (1.130 g,5.09 mmol) in one portion at room temperature under N₂. The reaction wasstirred at 90° C. for 8 h, then diluted with water (50 mL) and extractedwith EtOAc (50 mL×3). The combined organic layers were washed withbrine, dried over Na₂SO₄ and evaporated to dryness. The crude productwas purified by silica gel column (petroleum ether:EtOAc=5:1) to affordthe title compound as a white solid.

The two enantiomers were separated by chiral SFC method (Column:Chiralpak AD 250 mm*30 mm, 10 μm; Mobile phase: 35% MeOH+NH₃.H₂O; Flowrate: 80 mL/min; Wavelength: 280 nm). Both enantiomers (faster eluentIsomer 1 and slower eluent Isomer 2) have the same analytical data: LCMS(ESI) calculated for C₂₅H₂₇F₃N₃O₅S [M+H]⁺: 538, found: 538. ¹H-NMR(CDCl₃, 400 MHz) δ 7.69 (br s, 1H), 7.51 (d, J=8.0 Hz, 2H), 7.21 (d,J=8.0 Hz, 2H), 6.72 (d, J=9.0 Hz, 1H), 6.63 (brs, 1H), 4.19 (dd, J=1.7,14.3 Hz, 1H), 3.51 (d, J=4.5 Hz, 1H), 3.11 (dd, J=9.5, 14.0 Hz, 1H),2.33 (s, 3H), 1.70 (s, 6H), 1.58-1.66 (m, 1H), 1.48-1.56 (m, 1H),1.17-1.26 (m, 2H), 0.81-0.91 (m, 1H), 0.67-0.77 (m, 1H).

Step 6—Preparation of(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-((1-cyanocyclopropyl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamateand(R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-((1-cyanocyclopropyl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (R or S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-((1-cyanocyclopropyl)methyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(Isomer 1 from Step 5, 200 mg, 0.372 mmol) in MeOH (10 ml) was addedmagnesium (181 mg, 7.44 mmol) in one portion at 25° C. under nitrogen.The reaction was stirred at 25° C. for 18 hours, then quenched withsaturated NH₄Cl solution (80 mL) and extracted with EtOAc (3×70 mL). Theorganic layers were combined, dried over Na₂SO₄, filtered and thefiltrate concentrated in vacuum. The crude product was purified bypre-TLC (petroleum. ether/EtOAc=3:1) to afford the title compound(Isomer 1 from Step 6) as a white solid.

The other enantiomer (Isomer 2 from Step 6) was prepared using a similarprocedure starting with Isomer 2 from Step 5. Both enantiomers have thesame analytical data: LCMS (ESI) calculated for C₁₈H₂₁F₃N₃O₃ [M+H]⁺:384.1, found: 384.2.

Step 7—Preparation of(R)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-((1-cyanocyclopropyl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamateand(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-((1-cyanocyclopropyl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (R orS)-1,1,1-trifluoro-2-methylpropan-2-yl(2-((1-cyanocyclopropyl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(Isomer 1 from Step 6, 40 mg, 0.104 mmol) in pyridine (2 mL) and THF (2mL) was added 3-chloro-1-ethyl-1H-pyrazole-4-sulfonyl chloride (47.8 mg,0.209 mmol). The reaction was stirred at 25° C. for 18 h, thenconcentrated. The title compound (Isomer 1 of Step 7, Example 93A) wasobtained by prep-HPLC as a white solid.

The other enantiomer, Example 93B, was prepared using a similarprocedure from Isomer 2 from Step 6. Both enantiomers have the sameanalytical data: LCMS (ESI) calculated for C₂₃H₂₆ClF₃N₅O₅S [M+H]⁺:576.1, found: 576.1; ¹H-NMR (CDCl₃, 400 MHz) δ 8.08 (1H, s), 7.81 (1H,s), 6.77-6.82 (2H, m), 6.59 (1H, s), 4.27-4.31 (1H, m,), 4.21-4.22 (1H,m), 4.01-4.07 (2H, m), 3.40-3.45 (1H, m), 2.01-2.02 (2H, m), 1.69 (6H,s), 1.39-1.43 (3H, m), 1.23-1.27 (2H, m), 0.91-0.93 (1H, m), 0.81-0.83(2H, m).

Example 94—Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-cyano-2-methylpropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamateand (R)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-cyano-2-methylpropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(Examples 94A and 94B)

Step 1—Preparation of (R andS)-2,2-dimethyl-3-(oxiran-2-yl)propanenitrile

To a solution of isobutyronitrile (5 g, 72.4 mmol) in THF (10 mL) wasadded LDA (36.2 mL, 72.4 mmol) dropwise at −78° C. under nitrogen. After1 h, the reaction mixture was added dropwise to a solution of2-(bromomethyl)oxirane (9.91 g, 72.4 mmol) in THF (4 mL) at −78° C. Theresulting reaction was stirred at −78° C. for 3 h, then quenched withsaturated NH₄Cl solution (20 mL) and diluted with water (100 mL). Theaqueous layer was extracted with DCM (40 mL×3) and the combined organiclayers were washed with brine (40 mL×2), dried over Na₂SO₄ andevaporated to dryness. The crude product was purified by silica gelchromatography eluted with petroleum ether:EtOAc=50:1 to 40:1 to affordthe title product as yellow oil. ¹H NMR (CDCl₃, 400 MHz) δ 3.05-3.14 (m,1H), 2.80 (d, J=4.3 Hz, 1H), 2.45-2.53 (m, 1H), 1.81-1.90 (m, 1H),1.59-1.64 (m, 1H), 1.44 (s, 3H), 1.40 (s, 3H).

Step 2—Preparation of (R andS)-2,2-dimethyl-3-(6-nitro-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanenitrile

To a mixture of N-(2-fluoro-5-nitrophenyl)-4-methylbenzenesulfonamide (5g, 16.11 mmol) and (R and S)-2,2-dimethyl-3-(oxiran-2-yl)propanenitrile(5.04 g, 40.3 mmol) in DMF (50 mL) was added K₂CO₃ (6.68 g, 48.3 mmol)in one portion at room temperature under nitrogen. The resulting mixturewas stirred at 100° C. for 4 days, then diluted with water (200 mL) andextracted with EtOAc (50 mL×4). The combined organic layers were washedwith brine (50 mL×2), dried over Na₂SO₄, filtered and evaporated todryness. The crude product was purified by silica gel column (petroleumether:EtOAc=20:1 to 3:1) to afford the title product as a yellow oil.LCMS (ESI) calculated for C₂₀H₂₂N₃O₅S [M+H]⁺: 416, found: 416. ¹H NMR(CDCl₃, 400 MHz) δ 8.72 (d, J=2.4 Hz, 1H), 7.93 (dd, J=2.4, 9.0 Hz, 1H),7.60 (d, J=8.2 Hz, 2H), 7.29 (d, J=8.2 Hz, 2H), 6.91 (d, J=9.0 Hz, 1H),5.27 (s, 2H), 4.24 (dd, J=2.2, 14.3 Hz, 1H), 3.78-3.87 (m, 1H), 3.26(dd, J=9.2, 14.3 Hz, 1H), 2.38 (s, 3H), 1.78-1.86 (m, 1H), 1.68-1.75 (m,1H), 1.38 (s, 3H), 1.35 (s, 3H).

Step 3—Preparation of (R andS)-3-(6-amino-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2,2-dimethylpropanenitrile

To a solution of (R andS)-2,2-dimethyl-3-(6-nitro-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanenitrile(4.6 g, 11.07 mmol) in EtOAc (50 mL) were added di-tert-butyldicarbonate (3.62 g, 16.61 mmol) and Pd/C (0.46 g) at room temperatureunder nitrogen. The mixture was stirred at 25° C. overnight under H₂ (50psi), then filtered over CELITE and evaporated to dryness. The crudeproduct was purified by silica gel chromatography eluting with petroleumether:EtOAc=5:1 to afford the title product as a yellow solid. LCMS(ESI) calculated for C₂₅H₃₂N₃O₅S [M+H]⁺: 486, found: 486. ¹H NMR (CDCl₃,400 MHz) δ 7.64 (d, J=1.9 Hz, 1H), 7.55 (d, J=8.2 Hz, 2H), 7.25 (br s,2H), 6.73 (d, J=8.6 Hz, 1H), 6.40 (br s, 1H), 4.15 (dd, J=1.7, 14.2 Hz,1H), 3.56 (t, J=8.8 Hz, 1H), 3.18 (dd, J=9.6, 14.2 Hz, 1H), 2.36 (s,3H), 1.67-1.76 (m, 1H), 1.62 (dd, J=2.3, 14.8 Hz, 1H), 1.50 (s, 9H),1.33 (s, 3H), 1.31 (s, 3H).

Step 4—Preparation of (R andS)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-cyano-2-methylpropyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

A solution of (R and S)-tert-butyl(2-(2-cyano-2-methylpropyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(5.0 g, 10.38 mmol) in HCl in dioxane (4 M, 100 mL) was stirred at 25°C. for 1 h. The reaction solution was evaporated to dryness to give thecrude (R andS)-3-(6-amino-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2,2-dimethylpropanenitrileas brown oil. The crude product was used directly in the next stepwithout further purification.

To a solution of the above product (4.0 g, 10.38 mmol) in DMSO (40 mL)was added 1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate(2.42 g, 10.90 mmol) in one portion at room temperature under nitrogen.The mixture was stirred at 80° C. for 4 h, then diluted with water (50mL) and extracted with EtOAc (25 mL×3). The combined organic layers werewashed with brine, dried over Na₂SO₄ and evaporated to dryness. Thecrude product was purified by prep-TLC (petroleum ether:EtOAc=3:1) toafford the title as a yellow oil. LCMS (ESI) calculated forC₂₅H₂₉F₃N₃O₅S [M+H]⁺: 540, found: 540. ¹H NMR (CDCl₃, 400 MHz) δ 7.73(brs, 1H), 7.56 (d, J=8.2 Hz, 2H), 7.24 (s, 3H), 6.76 (d, J=8.6 Hz, 1H),6.61 (brs, 1H), 4.15 (dd, J=2.0, 14.1 Hz, 1H), 3.58 (t, J=8.6 Hz, 1H),3.19 (dd, J=9.4, 14.1 Hz, 1H), 2.37 (s, 3H), 1.75 (s, 6H), 1.69-1.73 (m,1H), 1.64 (d, J=2.4 Hz, 1H), 1.34 (s, 3H), 1.31 (s, 3H).

Step 5—Preparation of(S)-3,3-difluoro-2-methylbutan-2-yl(2-(2-cyano-2-methylpropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamateand (R)-3,3-difluoro-2-methylbutan-2-yl(2-(2-cyano-2-methylpropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (R andS)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-cyano-2-methylpropyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(4.5 g, 8.34 mmol) in MeOH (60 ml) was added magnesium (2.0 g, 83 mmol)in one portion at room temperature under nitrogen. The mixture wasstirred at 80° C. for 4 h, then diluted with MeOH (100 mL) and filtered.The resulting filtrate was evaporated to dryness and the crude productpurified by silica gel column (petroleum ether:EtOAc=15:1 to 2:1) toafford the product of the title racemate as a yellow oil.

The two enantiomers were separated by SFC method (column: Chiralpak AD-H250×4.6 mm I.D., Sum; Mobile phase: ethanol (0.05% DEA) in CO₂ from 5%to 40%; Flow rate: 2.35 mL/min wavelength: 220 nm). Isomer 1 RT=6.853min and Isomer 2 RT=7.966 min. Both enantiomers have the same analyticaldata: LCMS (ESI) calculated for C₁₈H₂₃F₃N₃O₃ [M+H]⁺: 386, found: 386. ¹HNMR (CDCl₃, 400 MHz) δ 6.81 (brs, 1H), 6.68 (d, J=8.6 Hz, 1H), 6.51 (brs, 1H), 6.42 (d, J=8.2 Hz, 1H), 4.34 (t, J=7.0 Hz, 1H), 3.39 (d, J=11.7Hz, 1H), 3.13 (dd, J=6.9, 11.5 Hz, 1H), 1.91 (dd, J=8.8, 14.7 Hz, 1H),1.73-1.78 (m, 1H), 1.71 (s, 6H), 1.47 (s, 3H), 1.41 (s, 3H).

Step 6—Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-cyano-2-methylpropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamateand (R)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-cyano-2-methylpropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (R orS)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-cyano-2-methylpropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(Isomer 1 from Step 5; 60 mg, 0.156 mmol, isomer 1) in THF (2 mL) wereadded pyridine (0.5 ml, 6.18 mmol) and3-chloro-1-ethyl-1H-pyrazole-4-sulfonyl chloride (150 mg, 0.655 mmol) inone portion at room temperature under nitrogen. The reaction was stirredat 60° C. overnight, then evaporated to dryness. The crude product waspurified by prep-TLC (petroleum ether:EtOAc=2:1) to afford the titlecompound (Example 94A) as a yellow oil.

The other enantiomer, (Example 94B) was prepared using a similarprocedure as described above starting with Isomer 2 from Step 5. Bothenantiomers have the same analytical data: LCMS (ESI) calculated forC₂₃H₂₈ClF₃N₅O₅S [M+H]⁺: 578, found: 578. ¹H NMR (CDCl₃, 400 MHz) δ 8.12(brs, 1H), 7.85 (brs, 1H), 6.78-6.87 (m, 2H), 6.75 (brs, 1H), 4.18-4.31(m, 2H), 4.07 (q, J=7.2 Hz, 2H), 3.45 (dd, J=8.4, 12.7 Hz, 1H), 1.88 (d,J=8.6 Hz, 1H), 1.78 (brs, 1H), 1.72 (br s, 6H), 1.40-1.47 (m, 9H).

Example 95—Preparation of Additional Gem-Dimethyl Propionic Nitriles

The compounds in Table 28 below were prepared based on the experimentalprocedures described in Example 94 and elsewhere in the detaileddescription, and can be achieved by one of skill in the art in light ofthe present disclosure.

TABLE 28 Ex. Observed No. Structure Name m/z 95A

(R)-1,1,1-trifluoro-2- methylpropan-2-yl (2-(2-cyano-2-methylpropyl)-4-((4-fluoro-3- (trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 612 (M + H)+ 95B

(R)-1,1,1-trifluoro-2- methylpropan-2-yl (2-(2-cyano-2-methylpropyl)-4-((4-fluoro-3- methoxyphenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 596 (M + Na)+ 95C

(R)-1,1,1-trifluoro-2- methylpropan-2-yl (2-(2-cyano-2-methylpropyl)-4-((4-fluoro-3- methylphenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 558 (M + H)+ 95D

(S)-1,1,1-trifluoro-2- methylpropan-2-yl (2-(2-cyano-2-methylpropyl)-4-((4-fluoro-3- methoxyphenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 596 (M + Na)+ 95E

(S)-1,1,1-trifluoro-2- methylpropan-2-yl (2-(2-cyano-2-methylpropyl)-4-((4-fluoro-3- methylphenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 580 (M + Na)+ 95F

(R)-1,1,1-trifluoro-2- methylpropan-2-yl (2-(2-cyano-2-methylpropyl)-4-((3-ethoxy- 1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 588(M + H)+ 95G

(S)-1,1,1-trifluoro-2- methylpropan-2-yl (2-(2-cyano-2-methylpropyl)-4-((3-ethoxy- 1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 588(M + H)+

Example 96—Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(3-(cyclopropanesulfonamido)-3-oxopropyl)-4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(Example 96)

To a solution of(S)-3-(4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoicacid (50 mg, 0.82 mmol) in DCM (1 mL) was added EDCI (32 mg, 0.17 mmol)and DMAP (20 mg, 0.17 mmol) at 0° C. The reaction was stirred at roomtemperature for 1 h, then cyclopropanesulfonamide (23 mg, 0.17 mmol) andDIPEA (21 mg, 0.17 mmol) were added. After stirring for 12 h at roomtemperature, the reaction mixture was diluted with water and 1N HCl,then extracted 3× with EtOAc. The combined organic layers were washedwith water, brine, dried over Na₂SO₄ and concentrated in vacuo. Thecrude product was purified by prep-HPLC (MeCN/water using TFA buffer) togive the title compound as a colorless oil. LCMS (ESI) calculated forC₂₆H₂₇F₇N₃O₈S₂ [M+H]⁺: 706, found: 706. ¹H-NMR (CDCl₃, 400 MHz) δ 8.28(1H, s), 8.09 (1H, d, J=4.4 Hz), 7.99 (1H, s), 7.86 (1H, s), 7.33-7.38(1H, m), 6.97 (1H, dd, J=2.0, 8.8 Hz), 6.78 (1H, d, J=9.2 Hz), 6.65 (1H,brs), 4.29 (1H, d, J=14.0 Hz), 3.73-3.75 (1H, m), 3.24 (1H, dd, J=9.6,13.6 Hz), 2.87-2.95 (1H, m), 2.49-2.60 (2H, m), 1.97-2.07 (1H, m),1.80-1.87 (1H, m), 1.76 (6H, s), 1.36-1.38 (2H, m), 1.10-1.12 (2H, m).

Example 97—Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl((S)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-((S)-3-(cyclopropanesulfonamido)-2-methyl-3-oxopropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamateand 1,1,1-trifluoro-2-methylpropan-2-yl((S)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-((R)-3-(cyclopropanesulfonamido)-2-methyl-3-oxopropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(Examples 97A and 97B)

A mixture of (S orR)-3-((S)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-methylpropanoicacid (50 mg, 0.086 mmol),2-(3H-[1,2,3]triazolo[4,5-b]pyridine-3-yl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (48.9 mg, 0.129 mmol) andN-ethyl-N-isopropylpropan-2-amine (33.3 mg, 0.257 mmol) in anhydrous DMF(0.5 mL) was stirred at 20° C. for 20 minutes, followed by the additionof cyclopropanesulfonamide (31.2 mg, 0.257 mmol). After stirring for 24hours, 2 mL water was added to the reaction and the resulting mixtureextracted with ethyl acetate (1.5 mL×3). The combined organic layerswere dried over anhydrous sodium sulfate, filtered and the filtrate wasconcentrated in vacuo. The crude product was purified by prep-HPLC(MeCN/water using TFA buffer) to afford the title compound (Example 97A)as a white solid. LCMS (ESI) calculated for C₂₅H₃₂ClF₃N₅O₈S₂ [M+H]⁺:686, found: 686. ¹H-NMR (CDCl₃, 400 MHz) δ 8.57 (1H, s), 8.19 (1H, s),7.89 (1H, s), 6.86-6.92 (2H, m), 6.77 (1H, s), 4.34 (1H, dd, J=14.0, 2.0Hz), 4.19 (2H, q, J=7.2 Hz), 4.06 (1H, br s), 3.41-3.57 (1H, m),2.98-3.01 (1H, m), 2.78-2.80 (1H, m), 2.05-2.15 (1H, m), 1.81 (6H, s),1.75-1.78 (1H, m), 1.55 (3H, t, J=7.6 Hz), 1.41-1.46 (1H, m), 1.27-1.37(3H, m), 1.13-1.21 (1H, m), 1.02-1.08 (1H, m)

The other diastereomer (Example 97B) was prepared using a similarprocedure as described above. LCMS (ESI) calculated for C₂₅H₃₂ClF₃N₅O₈S₂[M+H]⁺: 686, found: 686. ¹H-NMR (CDCl₃, 400 MHz) δ 8.56 (1H, s), 8.12(1H, s), 7.82 (1H, s), 6.81-6.84 (2H, m), 6.69 (1H, s), 4.37 (1H, d,J=13.6 Hz), 4.01-4.11 (4H, m), 3.26-3.30 (1H, m), 2.93-2.96 (1H, m),2.65-2.67 (1H, m), 2.02-2.09 (1H, m), 1.73 (6H, s), 1.44 (3H, t, J=7.2Hz), 1.32-1.40 (2H, m), 1.25 (3H, d, J=6.8 Hz), 1.11 (2H, d, J=8.0 Hz).

Example 98—Preparation of Additional Propionic Sulfonylamides ofBenzoxazines

The compounds in Table 29 below were prepared based on the experimentalprocedures described in Examples 96 and 97 and elsewhere in the detaileddescription, and can be achieved by one of skill in the art in light ofthe present disclosure.

TABLE 29 Ex. Observed No. Structure Name m/z 98A

2,2,2-trifluoro-1,1-dimethylethyl [(2S)-2-{3-[(tert-butylsulfonyl)amino]-3- oxopropyl}-4-{[4-fluoro-3-(trifluoromethyl)phenyl]sulfonyl}-3,4- dihydro-2H-1,4-benzoxazin-6-yl]carbamate 722 (M + H)+ 98B

2,2,2-trifluoro-1,1-dimethylethyl [(2S)- 4-{[4-fluoro-3-(trifluoromethyl)phenyl]sulfonyl}-2-(3-{[(4-methylphenyl)sulfonyl]amino}-3- oxopropyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbamate 756 (M + H)+ 98C

2,2,2-trifluoro-1,1-dimethylethyl [(2S)- 4-{[4-fluoro-3-(trifluoromethyl)phenyl]sulfonyl}-2-(3- oxo-3-{[(trifluoro-methyl)sulfonyl]amino}propyl)- 3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbamate 734 (M + H)+ 98D

1,1,1-trifluoro-2-methylpropan-2-yl ((S)-2-((R and S)-3-(cyclopropanesulfonamido)-2-methyl- 3-oxopropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 724 (M + Na)+ 98E

1,1,1-trifluoro-2-methylpropan-2-yl((S)-4-((3-chloro-1-ethyl-1H-pyrazol-4- yl)sulfonyl)-2-((R or S)-3-(1,1-dimethylethylsulfonamido)-2-methyl-3- oxopropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 702 (M + H)+ 98F

1,1,1-trifluoro-2-methylpropan-2-yl ((S)-2-((R or S)-3-(cyclopropanesulfonamido)-2-methyl- 3-oxopropyl)-4-((4-fluoro-3-methoxyphenyl)sulfonyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-6-yl)carbamate 704 (M + Na)+ 98G

1,1,1-trifluoro-2-methylpropan-2-yl ((S)-2-((R or S)-3-(1,1-dimethylethylsulfonamido)-2-methyl-3- oxopropyl)-4-((4-fluoro-3-methoxyphenyl)sulfonyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-6-yl)carbamate 698 (M + H)+ 98H

1,1,1-trifluoro-2-methylpropan-2-yl ((S)-2-((R or S)-3-(cyclopropanesulfonamido)-2-methyl- 3-oxopropyl)-4-((4-fluoro-3-methoxyphenyl)sulfonyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-6-yl)carbamate 704 (M + Na)+ 98i

1,1,1-trifluoro-2-methylpropan-2-yl ((S)-2-((R or S)-3-(1,1-dimethylethylsulfonamido)-2-methyl-3- oxopropyl)-4-((4-fluoro-3-methoxyphenyl)sulfonyl)-3,4-dihydro- 2H-benzo[b][1,4]oxazin-6-yl)carbamate 696 (M − H)− 98J

1,1,1-trifluoro-2-methylpropan-2-yl((S)-4-((3-chloro-1-ethyl-1H-pyrazol-4- yl)sulfonyl)-2-((R or S)-3-(1,1-dimethylethylsulfonamido)-2-methyl-3- oxopropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 702 (M + H)+

Example 99—Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-2-(oxetan-3-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(Example 99)

Step 1—Preparation of(S)-2-((4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl)propane-1,3-diol

To a solution of (S)-diethyl2-((4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl)malonate(700 mg, 1.58 mmol) in MeOH (20 mL) was added NaBH₄ (1.00 g, 26.4 mmol)in portions and the resulting mixture was stirred at 20° C. for 6 h. Thereaction was quenched with H₂O, extracted with EtOAc (3×50 mL), washedwith H₂O and brine and dried over Na₂SO₄. The combined organic layerswere concentrated in vacuo and purified by flash column chromatography(0-60% ethyl acetate in petroleum ether) to afford the title compound asyellow oil. LCMS (ESI) calculated for C₁₉H₂₃N₂O₅ [M+H]⁺: 359.2, found:359.1, ¹H NMR (400 MHz, CDCl₃) δ 7.47-7.56 (m, 2H), 7.21-7.33 (m, 3H),7.19 (s, 2H), 6.76 (d, J=8.2 Hz, 1H), 4.39-4.49 (m, 2H), 4.23 4.33 (m,1H), 3.65-3.86 (m, 4H), 3.20-3.31 (m, 1H), 3.04-3.16 (m, 1H), 1.69-1.80(m, 3H).

Step 2—Preparation of3-((S)-4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-(hydroxymethyl)propyl4-methylbenzenesulfonate

To a solution of(S)-2-((4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl)propane-1,3-diol(500 mg, 1.40 mmol) in 20 mL of THF was added butyllithium (1.0 mL, 1.4mmol) at −70° C. under N₂ and the reaction was stirred at −70° C. for 1h, then treated with 4-methylbenzene-1-sulfonyl chloride (300 mg, 1.57mmol) in 5 mL of THF. After 1 h at −70° C., the reaction was slowlywarmed to room temperature and stirred for an additional 2 h. Thereaction mixture was then quenched with aq. NH₄Cl, extracted with EtOAc(3×50 mL) and the combined organic layer was concentrated in vacuo. Thecrude product was purified by flash column chromatography (0-70% ethylacetate in petroleum ether) to afford the title compound as yellow oil.LCMS (ESI) calculated for C₂₆H₂₉N₂O₇S [M+H]⁺: 513.2, found: 513.2, ¹HNMR (400 MHz, CDCl₃) δ 7.71 (dd, J=8.0 Hz, 2.5 Hz, 2H), 7.43-7.54 (m,2H), 7.13-7.34 (m, 7H), 6.69 (t, J=8.8 Hz, 1H), 4.36-4.48 (m, 2H),4.01-4.26 (m, 3H), 3.54-3.71 (m, 2H), 3.22 (d, J=12.1 Hz, 1H), 2.99 3.10(m, 1H), 2.37 (d, J=2.7 Hz, 3H), 2.16 (d, J=5.5 Hz, 1H), 1.56-1.67 (m,2H).

Step 3—Preparation of(S)-4-benzyl-6-nitro-2-(oxetan-3-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

To a solution of3-((S)-4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-(hydroxymethyl)propyl4-methylbenzenesulfonate (650 mg, 1.27 mmol) in 20 mL of THF was addedsodium hydride (60%, 152 mg, 3.80 mmol) at 0° C. The reaction wasstirred at room temperature for 20 h, then quenched with aq.NH₄Cl andextracted with EtOAc (3×20 mL). The combined organic layer wasconcentrated in vacuo and the crude product was purified by flash columnchromatography (0-50% ethyl acetate in petroleum ether) to afford thetitle compound as yellow oil. LCMS (ESI) calculated for C₁₉H₂₁N₂O₄[M+H]⁺: 341.1, found: 341.1, ¹H NMR (400 MHz, CDCl₃) δ 7.35-7.51 (m,2H), 7.10-7.25 (m, 5H), 6.63 (d, J=8.6 Hz, 1H), 4.61-4.74 (m, 2H),4.21-4.41 (m, 4H), 4.00 (brs, 1H), 3.06-3.20 (m, 2H), 2.97 (dd, J=12.1Hz, 7.8 Hz, 1H), 1.89-2.00 (m, 1H), 1.85-1.74 (m, 1H).

Step 4—Preparation of(S)-2-(oxetan-3-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-amine

To a solution of(S)-4-benzyl-6-nitro-2-(oxetan-3-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine(400 mg, 1.18 mmol) in 20 mL of MeOH was added 10% Pd/C (300 mg, 2.82mmol), the reaction was stirred under H₂ (50 psi) for 4 h. The reactionmixture was then filtered and concentrated in vacuo to afford the titlecompound as brown oil. LCMS (ESI) calculated for C₁₂H₁₇N₂O₂ [M+H]⁺:221.1, found: 221.1.

Step 5—Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(oxetan-3-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of(S)-2-(oxetan-3-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-amine(250 mg, 1.14 mmol) in DMSO (5 mL) was added3-methyl-1-(((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)-1H-imidazol-3-iumiodide (413 mg, 1.14 mmol). The resulting mixture was stirred at roomtemperature for 0.5 h, then quenched with NH₄Cl (aq) and extracted withEtOAc (3×20 mL). The combined organic layer was concentrated in vacuoand the crude product was purified by flash column chromatography (0-40%ethyl acetate in petroleum ether) to afford the title compound as yellowoil. LCMS (ESI) calculated for C₁₇H₂₂F₃N₂O₄ [M+H]⁺: 375.1, found: 375.1,¹H NMR (400 MHz, DMSO) δ 9.38 (br s, 1H), 6.81 (br s, 1H), 6.50 (s, 2H),5.85 (br s, 1H), 4.59-4.75 (m, 2H), 4.33 (q, J=6.0 Hz, 2H), 3.89 (d,J=7.0 Hz, 1H), 3.16-3.26 (m, 2H), 2.87-2.96 (m, 1H), 1.88-2.03 (m, 2H),1.69 (s, 6H).

Step 6—Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-2-(oxetan-3-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(oxetan-3-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(30 mg, 0.080 mmol) in THF (4 mL) and pyridine (0.5 mL) was added4-fluoro-3-(trifluoromethyl)benzene-1-sulfonyl chloride (50 mg, 0.190mmol). The resulting mixture was stirred at 50° C. for 6 h, thenquenched with 10 mL of water and extracted with EtOAc (3×10 mL). Thecombined organic layers were concentrated in vacuo and the crude productwas purified by prep-HPLC to afford the title compound as a white solid.LCMS (ESI) calculated for C₂₄H₂₄F₇N₂O₆S [M+H]⁺: 601.1, found: 601.1, ¹HNMR (400 MHz, MeOD) 8.18 (d, J=7.4 Hz, 2H), 8.03 (br s, 1H), 7.53-7.59(m, 1H), 6.97 (dd, J=8.8 Hz, 2.2 Hz, 1H), 6.71 (d, J=9.0 Hz, 1H), 4.79(d, J=5.9 Hz, 2H), 4.45 (dd, J=11.3 Hz, 5.5 Hz, 2H), 4.32-4.37 (m, 1H),3.62 (brs, 1H), 3.35-3.39 (m, 1H), 3.23-3.29 (m, 1H), 1.95-2.05 (m, 2H),1.77 (s, 6H).

Example 100—Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(Example 100)

Step 1—Preparation of (S)-ethyl3-(4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoate

To a solution of (S)-diethyl2-((4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl)malonate(5 g, 11.30 mmol) in DMSO (50 mL) was added lithium chloride (2.395 g,56.5 mmol). The reaction was stirred at 170° C. for 10 hours, thencooled to room temperature and diluted with ethyl acetate (200 mL) andwashed with water (3×100 mL). The separated organic layers were driedwith Na₂SO₄ and concentrated under reduced pressure to give the crudeproduct, which was purified by flash column chromatography (petroleumether:ethyl acetate=10:1 to 5:1 to 3:1) to give the titled compound asorange oil. LCMS (ESI) calculated for C₂₀H₂₃N₂O₅ [M+H]⁺: 371.1, found:371.0.

Step 2—Preparation of(S)-3-(4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoicAcid

To a solution of ethyl3-(4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoate(500 mg, 1.350 mmol) in dioxane (5 mL) and water (3 mL) was addedlithium hydroxide (48.5 mg, 2.025 mmol). The reaction was stirred at 20°C. for 4 hours, then diluted with water (10 mL) and extracted with ethylacetate (3×5 mL). The aqueous layer was acidified with hydrochloric acid(1M, 10 mL) to pH=3 and extracted with ethyl acetate (10 mL×3). Thecombined organic layers were dried (Na₂SO₄), filtered and concentratedunder reduced pressure to give the titled compound as orange oil. LCMS(ESI) calculated for C₁₈H₁₉N₂O₅ [M+H]⁺: 343.1, found: 343.1; ¹H-NMR(CDCl₃, 400 MHz) δ 7.52 (2H, s), 7.24-7.31 (5H, m), 6.77-6.79 (1H, m),4.44 (2H, s), 4.22-4.24 (1H, m), 3.26-3.29 (1H, m), 3.08-3.13 (1H, m),2.58 (2H, s), 1.91-1.93 (2H, m).

Step 3—Preparation of(S)-2-(3-(4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoyl)hydrazinecarboxamide

To a solution of(S)-3-(4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoicacid (500 mg, 1.461 mmol) in deimethyl formamide (0.1 mL) and toluene (5ml) was added oxalyl dichloride (1.1 g, 8.76 mmol) dropwise. Thereaction was stirred at 20° C. for 10 minutes, then heated to 80° C. andstirred at this temperature for 1 hour. After cooling to 20° C., thereaction mixture was concentrated under reduced pressure. To a solutionof hydrazinecarboxamide (121 mg, 1.607 mmol) in tetrahydrofuran (10 mL)and water (2 mL) was added sodium hydroxide (117 mg, 2.92 mmol),followed by the slow addition of the crude product in tetrahydrofuran(10 mL) described above. The reaction was stirred at 0° C. for 2 hours,then concentrated to give the title compound as a red oil, which wasused in the next step without further purification. LCMS (ESI)calculated for C₁₉H₂₂N₅O₅ [M+H]⁺: 400.1, found: 400.1.

Step 4—Preparation of(S)-3-(2-(4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl)-1H-1,2,4-triazol-5(4H)-one

A solution of(S)-2-(3-(4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoyl)hydrazinecarboxamide(590 mg, 1.344 mmol) in 2M sodium hydroxide (20 mL), was stirred at 100°C. for 12 hours, then cooled to 20° C. and acidified with 1Mhydrochloric acid to pH=2. The resulting mixture was filtered andconcentrated to give the title compound as an orange solid. LCMS (ESI)calculated for C₁₉H₂₀N₅O₄ [M+H]⁺: 382.1, found: 382.1. ¹H-NMR (CDCl₃,400 MHz) δ 7.51 (2H, s), 7.23-7.31 (5H, m), 6.76-6.78 (1H, m), 4.43 (2H,s), 4.23 (1H, s), 3.13-3.29 (1H, m), 3.09-3.12 (1H, m), 2.71-2.76 (1H,m), 2.54-2.56 (1H, m), 1.90-1.98 (1H, m).

Step 5—Preparation of(S)-3-(2-(6-amino-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl)-1H-1,2,4-triazol-5(4H)-one

To a solution of(S)-3-(2-(4-benzyl-6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl)-1H-1,2,4-triazol-5(4H)-one(40 mg, 0.105 mmol) in methanol (15 mL) was added Pd(OH)₂ under argon.The mixture was degassed under hydrogen several times, and stirred at20° C. under H₂ balloon for 15 hours. The reaction was filtered andconcentrated under reduced pressure to give the title compound as a darkoil. LCMS (ESI) calculated for C₁₂H₁₆N₅O₂ [M+H]⁺: 262.1, found: 262.2.

Step 6—Preparation of(S)-4-(2,6-difluorobenzyl)-1-(4-fluorophenyl)-N—((R)-1-phenylethyl)piperazine-2-carboxamide

To a solution of(S)-3-(2-(6-amino-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl)-1H-1,2,4-triazol-5(4H)-one(20 mg, 0.077 mmol) in DMSO (3 mL) was added3-methyl-1-(((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)-1H-imidazol-3-iumiodide (21.79 mg, 0.092 mmol) and the reaction was stirred at 20° C. for20 minutes. The reaction mixture was directly purified by prep-HPLC(MeCN/H₂O as eluent, 0.05% TFA) to give the title compound as a whitesolid. LCMS (ESI) calculated for C₁₇H₂₁F₃N₅O₄ [M+H]⁺: 416.1, found:416.1.

Step 7—Preparation of(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(10 mg, 0.024 mmol) in tetrahydrofuran (5 mL) was added pyridine (1 mL)and 3-chloro-1-ethyl-1H-pyrazole-4-sulfonyl chloride (16.5 mg, 0.072mmol). The reaction was stirred at 15° C. for 3 hours, then directlypurified by pre-HPLC (MeCN/H₂O as eluent, 0.05% TFA) to give the titlecompound as a white solid. LCMS (ESI) calculated for C₂₂H₂₆ClF₃N₇O₆S[M+H]⁺: 608.1, found: 608.0; ¹H-NMR (CDCl₃, 400 MHz) δ 8.27 (1H, s),7.89 (1H, s), 6.92-6.95 (1H, m), 6.74-6.77 (1H, m), 4.34-4.37 (1H, m,),4.07-4.11 (2H, m), 3.89 (2H, s), 3.34-3.38 (1H, m), 2.69-2.74 (2H, m),1.92-2.01 (3H, m),1.74 (6H, s), 1.36-1.40 (3H, m).

Example 101—Preparation of(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(Example 101)

To a solution of(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(30 mg, 0.049 mmol) in DMF (2 mL) was added potassium carbonate (6.82mg, 0.049 mmol) and iodomethane (7.00 mg, 0.049 mmol) at 0° C. Thereaction was stirred at 25° C. for 2 hours, then concentrated andpurified by pre-HPLC (MeCN/H₂O as eluent, 0.05% TFA) to afford the titlecompound as a yellow solid. LCMS (ESI) calculated for C₂₃H₂₈ClF₃N₇O₆S[M+H]⁺: 622.1, found: 622.1; ¹H-NMR (CDCl₃, 400 MHz) δ 8.11 (1H, s),7.85 (1H, s), 6.88 (2H, s), 6.77-6.79 (1H, m), 4.38 (1H, d, J=13.2 Hz),4.08-4.10 (2H, m,), 3.64 (1H, s), 3.38-3.43 (1H, m), 3.23 (3H, s),2.70-2.76 (2H, m), 2.00-2.04 (2H, m), 1.74 (6H, s), 1.43-1.47 (3H, m).

Example 102—Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(Example 102)

Step 1—Preparation of(S)-3-(6-amino-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanenitrile

A mixture of(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-cyanoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(see Example 92; 100 mg, 0.18 mmol), LiOH.H₂O (84 mg, 2 mmol), dioxane(1 mL) and H₂O (1 mL) were stirred at 40° C. for 6 hours. The reactionmixture was extracted with EtOAc, dried over Na₂SO₄ and concentrated invacuo to give the crude title product as a white solid, which was usedin the next step without further purification. LCMS (ESI) calculated forC₁₈H₁₇F₃N₃O₃S [M+H]⁺: 412, found: 412.

Step 2—Preparation of (S)-tert-butyl(2-(2-cyanoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

A mixture of(S)-3-(6-amino-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanenitrile(100 mg, 0.24 mmol), Boc₂O (218 mg, 1 mmol), Et₃N (202 mg, 2 mmol) andDCM (10 mL) were stirred at 15° C. for 16 hours. The reaction mixturewas extracted with DCM and water and the organic layer washed withbrine, dried over Na₂SO₄ and concentrated in vacuo. The crude productwas purified by prep-TLC to give the title compound as a yellow solid.LCMS (ESI) calculated for C₂₃H₂₅F₃N₃O₅S [M+H]⁺: 512, found: 512.

Step 3—Preparation of(S,Z)-tert-butyl(2-(3-amino-3-(hydroxyimino)propyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

A mixture of (S)-tert-butyl(2-(2-cyanoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (20 mg, 0.04mmol), hydroxylamine hydrochloride (138 mg, 2 mmol), K₂CO₃ (1.38 g, 10mmol) and MeOH (10 mL) was stirred at 60° C. for 18 hours. The reactionmixture was concentrated in vacuo and extracted with water and EtOAc.The organic phase was washed with brine, dried over Na₂SO₄ andconcentrated. The crude product was purified by prep-TLC to give thetitle compound as a white solid. LCMS (ESI) calculated for C₂₃H₂₈F₃N₄O₆S[M+H]⁺: 545, found: 545. ¹H NMR (CDCl₃, 400 MHz) δ 7.94 (br s, 1H), 7.85(d, J=7.43 Hz, 1H), 7.75 (d, J=7.4 Hz, 1H), 7.69 (d, J=2.0 Hz, 1H),7.53-7.60 (m, 1H), 7.00-7.12 (m, 1H), 6.64-6.71 (m, 1H), 6.42 (br s,1H), 4.60 (br s, 1H), 4.20 (d, J=14.1 Hz, 1H), 3.43 (br s, 1H), 3.13(dd, J=9.8, 13.69 Hz, 1H), 2.15-2.32 (m, 2H), 1.68-1.78 (m, 2H),1.40-1.50 (m, 9H).

Step 4—Preparation of (S)-tert-butyl(2-(2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

A solution of (S,Z)-tert-butyl(2-(3-amino-3-(hydroxyimino)propyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(20 mg, 0.04 mmol) in MeCN (5 mL) was added pyridine (0.5 mL) andtriphosgene (6 mg, 0.02 mmol). After stirred for 18 hours at 15° C., thereaction mixture was concentrated in vacuo and extracted with EtOAc andwater. The organic phase was washed with brine, dried over Na₂SO₄ andconcentrated. The crude product was purified by prep-TLC (EtOAc) to givethe title compound as yellow oil. LCMS (ESI) calculated forC₂₄H₂₆F₃N₄O₇S [M+H]⁺: 571, found: 571. ¹H NMR (CDCl₃, 400 MHz) δ 9.52(br s, 1H), 7.95 (br s, 1H), 7.76-7.89 (m, 2H), 7.71 (d, J=2.0 Hz, 1H),7.54-7.63 (m, 1H), 7.03 (d, J=7.8 Hz, 1H), 6.66 (d, J=8.6 Hz, 1H), 6.40(br s, 1H), 4.02 (d, J=6.7 Hz, 1H), 3.50-3.60 (m, 1H), 3.22 (dd, J=9.2,13.9 Hz, 1H), 2.60-2.74 (m, 2H), 1.82-1.93 (m, 2H), 1.18 (s, 9H).

Step 5—Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

A solution of (S)-tert-butyl(2-(2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(57 mg, 0.1 mmol) in DCM (2 mL) was added TFA (1 mL). After stirred for1 hour at 15° C., the reaction mixture was concentrated in vacuo. Theaniline intermediate was next added to a solution of3-methyl-1-(((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)-1H-imidazol-3-iumiodide (73 mg, 0.2 mmol) in DMSO (2 mL). The reaction was stirred for 1h and the mixture was directly purified with prep-HPLC (MeCN/water usingTFA buffer) to give the title product as white solid. LCMS (ESI)calculated for C₂₄H₂₃F₆N₄O₇S [M+H]⁺: 625, found: 625. ¹H NMR (CD₃OD, 400MHz) δ 8.02-8.24 (m, 3H), 7.97 (d, J=7.5 Hz, 1H), 7.77 (t, J=8.0 Hz,1H), 7.03 (d, J=11.0 Hz, 1H), 6.74 (d, J=8.5 Hz, 1H), 4.41 (d, J=14.0Hz, 1H), 3.58 (brs, 1H),2.69-2.78 (m, 2H), 1.89-2.06 (m, 2H), 1.79 (s,6H).

Example 103—Preparation of(R)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-methyl-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamateand(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-methyl-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(Examples 103A and 103B)

Step 1—Preparation of (R andS)—N-hydroxy-2,2-dimethyl-3-(6-nitro-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanimidamide

To a stirred mixture of (R andS)-2,2-dimethyl-3-(6-nitro-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanenitrile(see Example 94; 3.0 g, 7.22 mmol) in EtOH (30 mL) was added NH₂OH.HCl(1.0 g, 14.39 mmol), K₂CO₃ (3.0 g, 21.71 mmol) and water (10 mL). Thereaction was heated to reflux for 18 hours, then cooled to roomtemperature and stirred for 30 minutes. The solid was filtered off anddried under vacuum to affordN-hydroxy-2,2-dimethyl-3-(6-nitro-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanimidamideas a white solid.

Step 2—Preparation of (R andS)-3-(2-methyl-1-(6-nitro-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propan-2-yl)-1,2,4-oxadiazol-5(2H)-one

To a stirred solution of (R andS)—N-hydroxy-2,2-dimethyl-3-(6-nitro-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanimidamide(900 mg, 2.007 mmol) in DMSO (10 mL) was added CDI (488 mg, 3.01 mmol)and K₂CO₃ (555 mg, 4.01 mmol). The reaction was stirred for 18 hours at20° C., then treated with water (10 mL) and extracted with EtOAc (15mL). The organic layers was evaporated and the crude product purified bychromatography silica gel (petroleum ether:EtOAc=2:1 to 1:2) to affordthe title compound as a light-yellow solid. LCMS (ESI) calculated forC₂₁H₂₃N₄O₇S [M+H]⁺: 475.1, found: 475.1; ¹H-NMR (CDCl₃, 400 MHz) δ 8.68(1H, d, J=2.4 Hz), 7.85 (1H, dd, J=9.2, 2.4 Hz), 7.45 (2H, d, J=8.4 Hz),7.22 (2H, d, J=8.0 Hz), 6.74 (1H, d, J=8.8 Hz), 4.17 (1H, dd, J=14.4,2.0 Hz), 3.49 (1H, t, J=7.6 Hz), 3.07-3.13 (1H, m), 2.32 (3H, s),1.82-1.86 (2H, m), 1.26 (6H, d, J=9.2 Hz).

Step 3—Preparation of (R andS)-3-(1-(6-amino-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-methylpropan-2-yl)-1,2,4-oxadiazol-5(2H)-one

To a stirred solution of (R andS)-3-(2-methyl-1-(6-nitro-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propan-2-yl)-1,2,4-oxadiazol-5(2H)-one(900 mg, 1.897 mmol) in MeOH (10 mL) was added water (1 mL), Zn (124 mg,1.897 mmol) and NH₄Cl (101 mg, 1.897 mmol). The reaction was stirred for2 hours at 20° C., then filtered and the filtrate concentrated. Thecrude product was washed with EtOAc and water (20 mL each). The organiclayer was concentrated to afford the title compound as a gray solid.LCMS (ESI) calculated for C₂₁H₂₅N₄O₅S [M+H]⁺: 445.1, found: 445.1.

Step 4—Preparation of (R and S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-methyl-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)propyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

A mixture of 1,1,1-trifluoro-2-methylpropan-2-yl1H-imidazole-1-carboxylate (19.99 mg, 0.090 mmol), (S andR)-3-(1-(6-amino-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-methylpropan-2-yl)-1,2,4-oxadiazol-5(4H)-one(20 mg, 0.045 mmol) and concentrated HCl (one drop) in DMSO (3 mL) wasstirred at 80° C. for 4 hours. Upon completion, the reaction mixture wasdiluted with water (10 mL), extracted with EtOAc (3×15 ml) and thecombined organic layers dried and concentrated in vacuo. The crudeproduct was purified by prep-TLC (DCM:MeOH=15:1) to give the titlecompound as a brown solid. LCMS (ESI) calculated for C₂₆H₃₀F₃N₄O₇S[M+H]⁺: 599.1, found: 599.1; ¹H-NMR (CDCl₃, 400 MHz) δ 7.70 (1H, s),7.51 (2H, d, J=8.0 Hz), 7.23 (1H, s), 7.13 (1H, d, J=8.4 Hz), 6.72 (1H,s), 6.54 (1H, d, J=8.4 Hz), 4.04 (1H, d, J=12.8 Hz), 3.39-3.40 (1H, m),3.14-3.20 (1H, m), 2.39 (3H, s), 1.81-1.83 (1H, m), 1.76 (6H, s),1.65-1.68 (1H, m), 1.32 (3H, s), 1.23 (3H, s).

Step 5—Preparation of (R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-methyl-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamateand (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-methyl-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

A mixture of (R andS)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-methyl-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)propyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(300 mg, 0.501 mmol) and magnesium (97 mg, 4.01 mmol) in MeOH (10 mL)was stirred at 15° C. for 36 hours. Upon completion, the reactionmixture was concentrated in vacuo, diluted with water (10 mL) andacidified with HCl (1M) to pH=2. The biphasic mixture was extracted withEtOAc (3×20 mL) and the combined organic layers dried over Na₂SO₄ andevaporated. The crude product was purified by prep-TLC to give the titleracemic compound as a colorless oil.

The above racemate was resolved by SFC purification (Instrument: TharSFC 350; Column: OD (250 mm*30 mm, 10 um); Mobile phase: 30%IPA+NH₃.H₂O; 80 mL/min; Wavelength: 220 nm) to give two enantiomers(faster eluent, Isomer 1 and slower eluent, Isomer 2), which have thesame analytical data: LCMS (ESI) calculated for C₁₉H₂₄F₃N₄O₅ [M+H]⁺:445.1, found: 445.1.

Step 6—Preparation of(R)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-methyl-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamateand(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-methyl-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a mixture of (R orS)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-methyl-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(Isomer 1 from Step 5, 10 mg, 0.023 mmol) in THF (2 mL) was added3-chloro-1-ethyl-1H-pyrazole-4-sulfonyl chloride (10.31 mg, 0.045 mmol)and pyridine (2 mL). The reaction mixture was stirred at 20° C. for 2hours, then concentrated in vacuo. The crude product was purified byprep-HPLC (MeCN/water using TFA buffer) to afford the title compound(Isomer 1 from Step 6, Example 103A) as a white solid.

The other enantiomer (Isomer 2 from Step 6, Example 103B) was preparedusing a similar procedure as described above from Isomer 2 from Step 5.Both enantiomers have the same analytical data: LCMS (ESI) calculatedfor C₂₄H₂₉ClF₃N₆O₇S [M+H]⁺: 637.1, found: 637.1; ¹H-NMR (Methanol-d4,400 MHz) δ 8.28 (1H, s), 7.90 (1H, s), 6.91 (1H, d, J=8.8 Hz), 6.54 (1H,d, J=8.4 Hz), 4.24 (1H, d, J=14.0 Hz), 4.12 (2H, q, J=7.2 Hz), 3.97 (1H,t, J=8.4 Hz), 3.35-3.41 (1H, m), 1.96-2.02 (1H, m), 1.84-1.88 (1H, m),1.75 (6H, s), 1.41 (3H, t, J=7.2 Hz), 1.35 (6H, s).

Example 104—Preparation of Additional 1,2,4-oxadiazolones

The compounds in Table 30 below were prepared based on the experimentalprocedures described in Examples 102 and 103 and elsewhere in thedetailed description, and can be achieved by one of skill in the art inlight of the present disclosure.

TABLE 30 Ex. Observed No. Structure Name m/z 104A

2,2,2-trifluoro-1,1- dimethylethyl [(2S)-2-[2-(5- oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethyl]-4-{[3- (trifluoromethyl)phenyl]sulfonyl}-3,4-dihydro-2H-1,4- benzoxazin-6-yl]carbamate 625 (M + H)+104B

2,2,2-trifluoro-1,1- dimethylethyl {(2S)-4-[(3-cyclopropylphenyl)sulfonyl]-2- [2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethyl]-3,4- dihydro-2H-1,4-benzoxazin-6- yl}carbamate 597(M + H)+ 104C

tert-butyl {(2S)-4-[(3- cyclopropylphenyl)sulfonyl]-2-[2-(5-oxo-4,5-dihydro-1,2,4- oxadiazol-3-yl)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6- yl}carbamate 487 (M + H—tBu)+ 104D

(S)-1,1,1-trifluoro-2- methylpropan-2-yl (4-((3-chloro-1-ethyl-1H-pyrazol-4- yl)sulfonyl)-2-(2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3- yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 610 (M + H)+ 104E

(S)-tert-butyl (4-((3-chloro-1- ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-(5-oxo-4,5- dihydro-1,2,4-oxadiazol-3-yl)ethyl)-3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)carbamate 577 (M +Na)+ 104F

(R)-1,1,1-trifluoro-2- methylpropan-2-yl (4-((3-chloro-1-ethyl-1H-pyrazol-4- yl)sulfonyl)-2-(2-methyl-2-(5-oxo-4,5-dihydro-1,2,4- oxadiazol-3-yl)propyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 637 (M + H)+ 104G

(R)-1,1,1-trifluoro-2- methylpropan-2-yl (4-((4- fluoro-3-methoxyphenyl)sulfonyl)-2-(2- methyl-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)propyl)- 3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 633 (M + H)+ 104H

(S)-1,1,1-trifluoro-2- methylpropan-2-yl (4-((3-chloro-1-ethyl-1H-pyrazol-4- yl)sulfonyl)-2-(2-methyl-2-(5-oxo-4,5-dihydro-1,2,4- oxadiazol-3-yl)propyl)-3,4- dihydro-2H-benzo[b][1,4]oxazin-6- yl)carbamate 637 (M + H)+ 104i

(S)-1,1,1-trifluoro-2- methylpropan-2-yl (4-((4- fluoro-3-methoxyphenyl)sulfonyl)-2-(2- methyl-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)propyl)- 3,4-dihydro-2H- benzo[b][1,4]oxazin-6-yl)carbamate 633 (M + H)+

Example 105—Preparation of(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(Example 105)

Step 1—Preparation of (S)-methyl3-(4-benzyl-6-((tert-butoxycarbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoate

To a mixture of (S)-dimethyl2-((4-benzyl-6-((tert-butoxycarbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methyl)malonate(10.00 g, 20.64 mmol) in DMSO (100 mL) was added LiCl (5.25 g, 124mmol). The reaction was stirred at 140° C. for 8 hours, cooled to 25°C., diluted with water (200 mL) and extracted with ethyl acetate (3×300mL). The organic layers were combined, dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude product was purified by columnchromatography (SiO₂, petroleum ether:EtOAc=20:1 to 5:1) to give thetitle compound as a light yellow solid. LCMS (ESI) calculated forC₂₄H₃₁N₂O₅ [M+H]⁺: 427, found: 427.2; ¹H NMR (CDCl₃, 400 MHz) δ7.26-7.37 (5H, m), 6.73 (2H, d, J=8.6 Hz), 6.60 (1H, d, J=6.7 Hz), 6.22(1H, br. s.), 4.44 (2H, s), 4.11 (1H, d, J=3.1 Hz), 3.68 (3H, s), 3.24(1H, d, J=10.2 Hz), 3.10 (1H, dd, J=11.5, 7.6 Hz), 2.55 (2H, q, J=8.0Hz), 1.89-1.98 (2H, m), 1.47 (9H, s).

Step 2—Preparation of (S)-tert-butyl(4-benzyl-2-(3-hydrazinyl-3-oxopropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a mixture of (S)-methyl3-(4-benzyl-6-((tert-butoxycarbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoate(3.0 g, 7.03 mmol) in ethanol (40 mL) was added hydrazine hydrate (20mL, 350 mmol) and Et₃N (2.94 mL, 21.10 mmol). The reaction mixture wasstirred at 80° C. for 2 hours, cooled to 25° C. and concentrated invacuo. The residual oil was diluted with H₂O (50 mL) and extracted withethyl acetate (3×30 mL). The organic layers were combined, dried overNa₂SO₄, filtered and concentrated. The crude product was purified bycolumn chromatography (SiO₂, petroleum ether:EtOAc=3:1 to 1:10) to givethe title compound as a yellow oil. LCMS (ESI) calculated for C₂₃H₃₁N₄O₄[M+H]⁺: 427, found: 427.2; ¹H NMR (CDCl₃, 400 MHz) δ 7.23-7.39 (5H, m),6.69-6.78 (2H, m), 6.64 (1H, br. s.), 6.37 (1H, br. s.), 4.44 (2H, s),4.12-4.17 (1H, m), 3.21-3.27 (1H, m), 3.10 (1H, dd, J=11.7, 7.8 Hz),2.35-2.46 (2H, m), 1.83-1.95 (2H, m), 1.48 (9H, s).

Step 3—Preparation of (S)-tert-butyl(4-benzyl-2-(2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a mixture of (S)-tert-butyl(4-benzyl-2-(3-hydrazinyl-3-oxopropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(2.75 g, 6.45 mmol) in DMF (30 mL) was added Et₃N (2.70 mL, 19.34 mmol)and CDI (1.568 g, 9.67 mmol). The reaction was stirred at 25° C. for 3hours, then diluted with water (100 mL) and extracted with ethyl acetate(3×50 mL). The organic layers were combined, dried over Na₂SO₄, filteredand concentrated in vacuo. The crude product was purified by columnchromatography (SiO₂, petroleum ether:EtOAc=10:1 to 3:1) to give thetitle compound as a yellow solid. LCMS (ESI) calculated for C₂₄H₂₉N₄O₅[M+H]⁺: 453, found: 453.1; ¹H NMR (CDCl₃, 400 MHz) δ 7.24-7.37 (5H, m),6.80 (1H, br. s.), 6.72 (1H, d, J=8.6 Hz), 6.59 (1H, d, J=7.0 Hz), 6.29(1H, br. s.), 4.43 (2H, s), 4.15-4.20 (1H, m), 3.21-3.27 (1H, m), 3.09(1H, dd, J=11.5, 7.6 Hz), 2.73-2.84 (2H, m), 1.89-2.02 (2H, m), 1.47(9H, s).

Step 4—Preparation of(S)-5-(2-(6-amino-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl)-1,3,4-oxadiazol-2(3H)-one

To a solution of (S)-tert-butyl(4-benzyl-2-(2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(2.86 g, 6.32 mmol) in DCM (30 mL) was added TFA (20 mL, 269 mmol), Thereaction was stirred for 1 hour at 25° C., then concentrated in vacuo.The residual oil was diluted with DCM (50 mL), poured into aqueousNaHCO₃ and extracted with DCM (3×30 mL). The organic layers werecombined, dried over Na₂SO₄, filtered and concentrated to afford thetitle compound as brown oil, which was used directly in the next stepwithout further purification. LCMS (ESI) calculated for C₁₉H₂₁N₄O₃[M+H]⁺: 353, found: 353.1; ¹H NMR (MeOD, 400 MHz) δ 7.17-7.34 (6H, m),6.58 (1H, s), 6.29 (1H, s), 4.44 (2H, q, J=16.4 Hz), 3.14 (1H, dd,J=11.5, 7.6 Hz), 2.67-2.85 (2H, m), 1.93-1.99 (2H, m).

Step 5—Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-benzyl-2-(2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a mixture of(S)-5-(2-(6-amino-4-benzyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)ethyl)-1,3,4-oxadiazol-2(3H)-one(2.05 g, 5.82 mmol) in DMSO (20 mL) was added1,1,1-trifluoro-2-methylpropan-2-yl 1H-imidazole-1-carboxylate (1.551 g,6.98 mmol) and concentrated HCl (0.25 mL, 3.04 mmol). The reaction wasstirred at 80° C. for 5 hours, then diluted with water (50 mL) andextracted with ethyl acetate (3×30 mL). The organic layers werecombined, dried over Na₂SO₄, filtered and concentrated in vacuo. Thecrude product was purified by column chromatography (SiO₂, petroleumether:EtOAc=10:1 to 2:1) to give the title compound as yellow oil. LCMS(ESI) calculated for C₂₄H₂₆F₃N₄O₅ [M+H]⁺: 507, found: 507.2; ¹H NMR(CDCl₃, 400 MHz) δ 7.26-7.37 (5H, m), 6.71-6.80 (2H, m), 6.63 (1H, br.s.), 6.49 (1H, br. s.), 4.44 (2H, s), 4.16-4.20 (1H, m), 3.26 (1H, dd,J=11.7, 2.3 Hz), 3.12 (1H, dd, J=11.7, 7.4 Hz), 2.74-2.86 (2H, m),1.91-2.02 (2H, m), 1.72 (6H, s).

Step 6—Preparation of(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a mixture of(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-benzyl-2-(2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate (2.72 g, 5.37 mmol) in THF (100 mL) was added Pd/C (10%, 0.50g, 0.470 mmol) under argon. The suspension was degassed under vacuum andpurged with H₂ several times. The reaction was stirred under H₂ balloon(1 atm) at 25° C. for 12 hours, then filtered through a pad of CELITEand the filtrate concentrated to dryness to afford the title compound asa yellow solid, which was used directly in the next step without furtherpurification. LCMS (ESI) calculated for C₁₇H₂₀F₃N₄O₅ [M+H]⁺: 417, found:417.2; ¹H NMR (MeOD, 400 MHz) δ 6.77 (1H, br. s.), 6.47-6.58 (2H, m),4.03 (1H, q, J=5.9 Hz), 3.32 (1H, d, J=2.0 Hz), 3.03 (1H, dd, J=11.9,7.6 Hz), 2.71-2.82 (2H, m), 1.96 (2H, q, J=7.4 Hz), 1.70 (6H, s).

Step 7—Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a mixture of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(30 mg, 0.072 mmol) in THF (1.0 mL) was added3-chloro-1-ethyl-1H-pyrazole-4-sulfonyl chloride (33.0 mg, 0.144 mmol)and pyridine (1.0 mL). The reaction was stirred at 25° C. for 12 hours,then diluted with EtOAc (5 mL) and water (10 mL). The aqueous layer wasextracted with EtOAc (3×5 mL). The combined organic phase was dried overNa₂SO₄ and concentrated in vacuo. The crude product was purified byprep-HPLC (MeCN/water using TFA buffer) to afford the title compound asa white solid. LCMS (ESI) calculated for C₂₂H₂₅ClF₃N₆O₇S [M+H]⁺: 609,found: 609.1; ¹H NMR (MeOD, 400 MHz) δ 9.39 (1H, br. s.), 8.34 (1H, t,J=7.6 Hz), 8.11 (1H, br. s.), 6.77-6.87 (2H, m), 6.73 (1H, s), 4.40 (1H,dd, J=13.7, 1.6 Hz), 4.00-4.13 (3H, m), 3.40 (1H, dd, J=13.7, 9.0 Hz),2.78-2.87 (2H, m), 2.01-2.14 (2H, m), 1.75 (6H, s), 1.47 (3H, t, J=7.2Hz).

Example 106—Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-methyl-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(Example 106)

Step 1—Preparation of(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-cyano-2-methylpropyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

(R andS)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-cyano-2-methylpropyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(see Example 94; 46 g, 84.5 mmol) was resolved by SFC (Column: ChiralpakAD (250×30 mm I.D., 10 um); Mobile phase: Supercritical CO₂/MeOH (0.1%)NH₃.H₂O=70/30 at 80 mL/min; Column Temp: 38° C.; Nozzle Pressure: 100Ba; Wavelength: 220 nm) to give the titled compound (faster eluent,Isomer 1) as yellow solid. LCMS (ESI) calculated for C₂₅H₂₉F₃N₃O₅S[M+H]⁺: 540.2, found: 540.2.

Step 2—Preparation of(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2,2-dimethyl-3-oxopropyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-cyano-2-methylpropyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(10 g, 18.53 mmol) in toluene (600 mL) was added DIBAL-H (74.1 ml, 74.1mmol) dropwise at −78° C. under nitrogen. The reaction was stirred at−78° C. for 1 h, then quenched with MeOH (74 mL) and acidified with 1MHCl (244 mL). After stirring at 0° C. for 10 min, the resulting solutionwas extracted with EtOAc (500 mL×3) and the combined organic layerswashed with brine, dried over Na₂SO₄ and evaporated to dryness. Thecrude product was purified by column chromatography (petroleumether:ethyl acetate=3:1) to give the title compound as yellow solid.LCMS (ESI) calculated for C₂₅H₃₀F₃N₂O₆S [M+H]⁺: 543.2, found: 543.1.

Step 3—Preparation of(S)-2,2-dimethyl-3-(4-tosyl-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoicAcid

To a solution of(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2,2-dimethyl-3-oxopropyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(10.5 g, 19.35 mmol) in THF (400 mL) and water (80 mL) were addedsulfamic acid (11.27 g, 116 mmol), potassium dihydrogenphosphate (31.6g, 232 mmol) and sodium chlorite (2.63 g, 29.0 mmol) at 0° C. Thereaction was stirred at 0° C. for 1 h, then diluted with water (250 mL)and extracted with EtOAc (3×500 mL). The combined organic layers weredried over Na₂SO₄ and evaporated to dryness. The crude product waspurified by column chromatography (petroleum ether:ethyl acetate=10:1 to1:1) to afford the title compound as yellow solid. LCMS (ESI) calculatedfor C₂₅H₃₀F₃N₂O₇S [M+H]⁺: 559.2, found: 559.2.

Step 4—Preparation of (S)-tert-butyl2-(2,2-dimethyl-3-(4-tosyl-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoyl)hydrazinecarboxylate

To a solution of(S)-2,2-dimethyl-3-(4-tosyl-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoicacid (650 mg, 1.164 mmol) and Et₃N (0.250 mL, 1.790 mmol) in CH₂Cl₂ (15mL) was added HATU (442 mg, 1.164 mmol). The mixture was stirred at 25°C. for 1 h, then treated with tert-butyl hydrazinecarboxylate (237 mg,1.790 mmol). The mixture was stirred at 25° C. for 16 h, concentratedand the solid residue was purified by column chromatography (petroleumether:EtOAc=2:1) to give the title compound as colorless oil. LCMS (ESI)calculated for C₃₀H₄₀F₃N₄O₈S [M+H]⁺: 673.2, found: 673.2.

Step 5—Preparation of(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(3-hydrazinyl-2,2-dimethyl-3-oxopropyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (S)-tert-butyl2-(2,2-dimethyl-3-(4-tosyl-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)propanoyl)hydrazinecarboxylate(430 mg, 0.639 mmol) in ethyl acetate (3 ml) was added a solution of HClin EtOAc (10 ml, 4 M). The reaction was stirred at 20° C. for 2 h, thenconcentrated to give the crude title compound as light yellow solid.LCMS (ESI) calculated for C₂₅H₃₂F₃N₄O₆S [M+H]⁺: 573.2, found: 573.1.

Step 6-Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-methyl-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(3-hydrazinyl-2,2-dimethyl-3-oxopropyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(376 mg, 0.657 mmol) and N-ethyl-N-isopropylpropan-2-amine (255 mg,1.970 mmol) in DMF (5 mL) was added di(1H-imidazol-1-yl)methanone (160mg, 0.985 mmol). The reaction was stirred at 25° C. for 6 h, thenconcentrated in vacuo. The crude product was purified by prep-TLC(petroleum ether:EtOAc=1:1) to give the title compound as yellow oil.LCMS (ESI) calculated for C₂₆H₃₀F₃N₄O₇S [M+H]⁺: 599.2, found: 599.2.

Step 7—Preparation of(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-methyl-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-methyl-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(340 mg, 0.568 mmol) in MeOH (20 mL) was added Mg (276 mg, 11.36 mmol)in one portion at 25° C. under nitrogen. The reaction was stirred at 25°C. for 18 hours, then quenched with saturated NH₄Cl solution andextracted with EtOAc (3×300 mL). The combined organic layers were driedover Na₂SO₄, filtered and the filtrate concentrated in vacuo. The crudeproduct was purified by prep-TLC (petroleum ether:EtOAc=1:1) to affordthe title compound as yellow solid. LCMS (ESI) calculated forC₁₉H₂₄F₃N₄O₅ [M+H]⁺: 445.2, found: 445.2; ¹H-NMR (400 MHz, MeOD) δ 6.85(1H, s), 6.54 (1H, d, J=7.6 Hz), 6.39 (1H, d, J=8.8 Hz), 4.07-4.12 (1H,m), 3.24-3.25 (1H, m), 3.01-3.09 (2H, m), 1.99-2.08 (2H, m), 1.70 (6H,s), 1.25-1.41 (6H, m), 0.93-0.95 (1H, m).

Step 8—Preparation of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-methyl-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a mixture of (S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-methyl-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(30 mg, 0.068 mmol) in THF (0.5 mL) was added3-chloro-1-ethyl-1H-pyrazole-4-sulfonyl chloride (30.9 mg, 0.135 mmol)and pyridine (0.5 mL). The reaction mixture was stirred at 20° C. for 6hours, then diluted with water (3 mL) and extracted with ethyl acetate(3×5 mL). The organic layers were combined, dried over anhydrousmagnesium sulfate, filtered and concentrated in vacuo. The crude productwas purified by prep-HPLC (MeCN/water using TFA buffer) to afford thetitle compound as white solid. LCMS (ESI) calculated for C₂₄H₂₉ClF₃N₆O₇S[M+H]⁺: 637.1, found: 637.1; ¹H-NMR (400 MHz, MeOD) δ 8.24 (1H, s), 7.87(1H, s), 6.90-6.93 (1H, m), 6.52 (1H, d, J=9.2 Hz), 4.23 (1H, d, J=12.4Hz), 4.10 (2H, q, J=7.2 Hz), 3.87-3.92 (1H, m), 3.33-3.36 (1H, m),1.96-2.02 (1H, m), 1.81-1.84 (1H, m), 1.74 (6H, s), 1.32-1.41 (9H, m).

Example 107—Preparation of Additional 1,3,4-oxadiazolone

The compounds in Table 31 below were prepared based on the experimentalprocedures described in Examples 105 and 106 and elsewhere in thedetailed description, and can be achieved by one of skill in the art inlight of the present disclosure.

TABLE 31 Ex. Observed No. Structure Name m/z 107A

2,2,2-trifluoro-1,1- dimethylethyl {(2S)-4-[(3-cyclopropylphenyl)sulfonyl]- 2-[2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)ethyl]- 3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbamate 597 (M + H)+ 107B

2,2,2-trifluoro-1,1- dimethylethyl {(2S)-4-[(4- fluoro-3-methoxyphenyl)sulfonyl]- 2-[2-methyl-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2- yl)propyl]-3,4-dihydro-2H- 1,4-benzoxazin-6-yl}carbamate 633 (M + H)+

Example 108—Preparation of(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-(1H-tetrazol-5-yl)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(Example 108)

To a solution of(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-cyanoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(50 mg, 0.08 mmol) and sodium azide (28.7 mg, 0.4 mmol) in DMF (1 mL)was added NH₄Cl (23.6 mg, 0.4 mmol). The reaction was stirred at 110° C.for 6 h under N₂, then cooled and treated with water (10 mL). Thebiphasic mixture was extracted with ethyl acetate (10 mL) and thecombined organic layers were washed with aqueous sodium hydroxide (10mL), dried (Na₂SO₄), filtered and evaporated under reduced pressure. Thecrude product was purified by prep-HPLC (MeCN/water using TFA buffer) toafford the title compound as white solid. LCMS (ESI) calculated forC₂₃H₂₃F₆N₆O₅S [M+H]⁺: 609, found: 609. ¹H NMR (CDCl₃, 400 MHz) δ 7.95(brs, 1H), 7.74-7.90 (m, 3H), 7.54-7.63 (m, 1H), 6.91-7.00 (m, 1H),6.52-6.72 (m, 2H), 4.16 (d, J=12.9 Hz, 1H), 3.58 (brs, 1H), 3.23-3.35(m, 1H), 3.07 (t, J=6.8 Hz, 2H), 1.97-2.09 (m, 2H), 1.70 (brs, 7H).

Example 109—Preparation of Additional Tetrazoles

The compounds in Table 32 below were prepared based on the experimentalprocedures described in Example 108 and elsewhere in the detaileddescription, and can be achieved by one of skill in the art in light ofthe present disclosure.

TABLE 32 Ex. Observed No. Structure Name m/z 109A

2,2,2-trifluoro-1,1-dimethylethyl {(2S)-4-[(3-cyclopropylphenyl)sulfonyl]-2-[2- (1H-tetrazol-5-yl)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6- yl}carbamate 581 (M + H)+ 109B

2,2,2-trifluoro-1,1-dimethylethyl [(2S)-2-[2-(1H-tetrazol-5-yl)ethyl]-4-{[2-(trifluoromethyl)pyridin-4- yl]sulfonyl}-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbamate 610 (M + H)+ 109C

(S)-1,1,1-trifluoro-2-methylpropan- 2-yl (2-(2-(1H-tetrazol-5-yl)ethyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4- yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate 593 (M + H)+

Example 110—Preparation of(R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(hydroxymethyl)-5-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(Example 110)

Step 1—Preparation of(R)-(5-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methanol

(S)-2-(chloromethyl)oxirane (902 mg, 9.74 mmol) was added dropwise to astirred mixture of 2-amino-3-methylphenol (1.00 g, 8.12 mmol) and AcOH(1.40 mL, 24.4 mmol) in ethanol (50 mL) at 100° C. under nitrogen andthe resulting mixture was stirred at 100° C. for 1 h. K₂CO₃ (6.73 g,48.7 mmol) was next added and the resulting solution was stirred at 100°C. for an additional 16 h. The reaction was evaporated under reducedpressure and the residue dissolved in EtOAc, washed with water and brine(50 mL), dried over Na₂SO₄, filtered and concentrated. The crude productwas purified by silica gel column chromatography (EtOAc in petroleumether from 0 to 33%) to afford the title compound as brown oil.

Step 2—Preparation of(R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine

A solution of(R)-(5-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methanol (450 mg,2.51 mmol), 1H-imidazole (400 mg, 5.88 mmol) andtert-butylchlorodimethylsilane (700 mg, 4.64 mmol) in DMF (2 mL) wasstirred at 40-50° C. for 6 h. The reaction was then cooled and dilutedwith EtOAc, washed with brine, dried Na₂SO₄, filtered and concentrated.The crude product was purified by column chromatography on silica gel(EtOAc:petroleum ether=1:20-1:5) to afford the title compound as ayellow oil. LCMS (ESI) calculated for C₁₆H₂₈NO₂Si [M+H]⁺: 294.2, found:294.1, ¹H NMR (400 MHz, DMSO) δ 6.53 (dd, J=15.6 Hz, 7.4 Hz, 2H),6.34-6.45 (m, 1H), 5.16 (s, 1H), 3.95 (d, J=5.3 Hz, 1H), 3.65-3.85 (m,2H), 3.38 (d, J=2.7 Hz, 1H), 3.32 (s, 1H), 3.00-3.15 (m, 1H), 2.03 (s,3H), 0.88 (s, 9H), 0.07 (d, J=4.7 Hz, 6H).

Step 3—Preparation of(R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine

A solution of(R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine(100 mg, 0.341 mmol) and 3-(trifluoromethyl)benzene-1-sulfonyl chloride(100 mg, 0.409 mmol) in DCM (1 mL) and pyridine (1 mL) was stirred atroom temperature for 16 h. The reaction was then acidified with 0.5 MHCl to pH=5-6 and extracted with EtOAc. The combined organic layers werewashed with brine, dried with Na₂SO₄ and concentrated. The crude productwas purified by column chromatography on silica gel to afford the titlecompound as a yellow oil. LCMS (ESI) calculated for C₂₃H₃₁F₃NO₄SSi[M+H]⁺: 502.2, found: 502.2, ¹H NMR (400 MHz, CDCl₃) δ 7.77-7.90 (m,3H), 7.55-7.66 (m, 1H), 7.05-7.13 (m, 1H), 6.89 (d, J=7.4 Hz, 1H), 6.61(d, J=8.0 Hz, 1H), 4.24 (d, J=12.3 Hz, 1H), 3.88 (dd, J=10.4 Hz, 4.7 Hz,1H), 3.49-3.65 (m, 2H), 3.30 (s, 1H), 2.51 (s, 3H), 0.81 (s, 10H), 0.00(s, 3H), −0.03 (s, 3H).

Step 4—Preparation of(R)-(5-methyl-6-nitro-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methanol

To a solution of(R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-5-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine(300 mg, 0.598 mmol) in MeNO₂ (2 mL) was added nitroniumtetrafluoroborate (100 mg, 0.753 mmol) in one batch, then the reactionmixture was stirred at 0° C. for 3 h. The reaction mixture was directlypurified by preparative TLC to afford the title compound as a whitesolid. LCMS (ESI) calculated for C₁₇H₁₆F₃N₂O₆S [M+H]⁺: 433.1, found:433.2, ¹H NMR (400 MHz, CDCl₃) δ 7.88-8.00 (m, 4H), 7.62-7.73 (m, 1H),6.82 (d, J=9.2 Hz, 1H), 4.19-4.29 (m, 1H), 3.60-3.84 (m, 3H), 3.28-3.41(m, 1H), 2.60-2.67 (m, 3H).

Step 5—Preparation of (R)-(6-amino-5-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methanol

HCl (2.0 Min MeOH, 1.0 mL) was added to a solution of(R)-(5-methyl-6-nitro-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methanol(120 mg, 0.278 mmol) and iron powder (150 mg, 2.69 mmol) in methanol (2mL) and the resulting solution was stirred at room temperature for 1 h.The reaction was next filtered through CELITE and washed with methanol.The filtrate was concentrated to afford the title compound. LCMS (ESI)calculated for C₁₇H₁₈F₃N₂O₄S [M+H]⁺: 403.1, found: 403.0.

Step 6—Preparation of (R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(hydroxymethyl)-5-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of(R)-(6-amino-5-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)methanol(100 mg, 0.249 mmol) in DMSO (1 mL) was added(1-(((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)-1H-imidazol-3-ium-3-yl)methanideiodide (117 mg, 0.323 mmol) and the resultant mixture was stirred atroom temperature for 1 h. Water was then added and the biphasic mixtureextracted with EtOAc (10 mL×2). The combined organic layers were washedwith water and brine, concentrated and the crude product purified bypreparative HPLC (MeCN/water using TFA buffer) to afford the titlecompound as a white solid. LCMS (ESI) calculated for C₂₂H₂₃F₆N₂O₆S[M+H]⁺: 557.1, found: 557.2, ¹H NMR (400 MHz, CDCl₃) δ 7.40-7.97 (m,4H), 6.68 (d, J=8.4 Hz, 1H), 6.50 (s, 1H), 4.24 (d, J=12.5 Hz, 1H), 3.87(s, 1H), 3.65 (d, J=11.9 Hz, 1H), 3.19-3.39 (m, 1H), 2.38 (s, 3H), 1.77(d, J=6.3 Hz, 6H).

Example 111—Preparation of (R)-1,1,1-trifluoro-2-methylpropan-2-yl(5-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((ethylsulfonyl)methyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamateand (S)-1,1,1-trifluoro-2-methylpropan-2-yl(5-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((ethylsulfonyl)methyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate(Examples 111A and 111B)

Step 1—Preparation of1-benzyl-7-chloro-3,4-dihydro-1,5-naphthyridin-2(1H)-one

To a 0° C. solution of 7-chloro-3,4-dihydro-1,5-naphthyridin-2(1H)-one(2 g, 10.95 mmol) in N,N-dimethylformamide (20 mL) was added Cs₂CO₃(5.35 g, 16.43 mmol), followed by (bromomethyl)benzene (2.061 g, 12.05mmol). The reaction mixture was stirred at room temperature for 1 hour,then poured into water (50 mL) and extracted with EtOAc (50 ml×3). Thecombined organic layers were washed with brine (50 ml×3), dried overanhydrous Na₂SO₄ and concentrated under vacuum. The crude product waspurified by column chromatography on silica gel (EtOAc:petroleumether=0-30%) to afford the titled compound as a yellow solid. LCMS (ESI)calculated for C₁₅H₁₄ClN₂O [M+H]⁺: 273, found: 273. ¹HNMR (400 MHz,CDCl₃) δ 8.12 (1H, s), 7.26-7.36 (3H, m), 7.19 (2H, d, J=7.2 Hz), 7.11(1H, s), 5.11 (2H, s), 3.18 (2H, t, J=7.6 Hz), 2.90 (2H, t, J=8.0 Hz).

Step 2—Preparation of (R andS)-1-benzyl-7-chloro-2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridine-3-carboxylate

To a −78° C. solution of1-benzyl-7-chloro-3,4-dihydro-1,5-naphthyridin-2(1H)-one (2 g, 7.33mmol) in dry tetrahydrofuran (50 mL) was added LHMDS (8.80 mL, 8.80mmol, 1M in THF) and the mixture was stirred at −78° C. for 30 minutes.Methyl carbonochloridate (0.832 g, 8.80 mmol) was next added and thereaction was stirred at −78° C. for an additional 1 hour. The reactionwas quenched with saturated aq. NH₄Cl (20 mL) and extracted with EtOAc(50 mL×3). The combined organic layers were washed with brine (50 mL×3),dried over anhydrous Na₂SO₄ and concentrated under vacuum. The crudeproduct was purified by column chromatography on silica gel(EtOAc:petroleum ether=0-30%) to afford the titled compound as a yellowsolid. LCMS (ESI) calculated for C₁₇H₁₆ClN₂O₃ [M+H]⁺: 331, found: 331.¹HNMR (400 MHz, CDCl₃) δ 8.15 (1H, s), 7.25-7.35 (5H, m), 7.13 (1H, s),5.31 (1H, d, J=16.4 Hz), 5.31 (1H, d, J=16.4 Hz), 3.91 (1H, t, J=6.8Hz), 3.78 (3H, s), 3.58 (1H, dd, J=7.2 Hz J=16.4 Hz), 3.40 (1H, dd,J=6.4 Hz J=17.2 Hz).

Step 3—Preparation of (R andS)-1-benzyl-7-chloro-3-(methoxymethyl)-1,2,3,4-tetrahydro-1,5-naphthyridine

To a 0° C. solution of methyl1-benzyl-7-chloro-2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridine-3-carboxylate(1.7 g, 5.14 mmol) in dry tetrahydrofuran (50 mL) was added BH₃—SMe₂(2.440 mL, 25.7 mmol). The reaction mixture was stirred at 60° C. for 2hours, then quenched with MeOH (10 mL) and concentrated under vacuum.The crude product was purified by column chromatography on silica gel(EtOAc:petroleum ether=0-30%) to afford the titled compound as a yellowsolid. LCMS (ESI) calculated for C₁₆H₁₈ClN₂O [M+H]⁺: 289, found: 289.¹HNMR (400 MHz, CDCl₃) δ 7.80 (1H, d, J=1.6 Hz), 7.10-7.31 (5H, m), 6.82(1H, d, J=2.0 Hz), 4.45 (2H, q, J=16.8, 27.2 Hz), 3.77 (1H, d, J=10.8Hz), 3.48-3.52 (3H, m), 3.28 (1H, t, J=9.2 Hz), 2.79 (1H, q, J=10.0,18.4 Hz), 2.27-2.29 (1H, m), 1.56-1.54 (1H, m).

Step 4—Preparation of (R andS)-(1-benzyl-7-chloro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methylmethanesulfonate

To a solution of (R andS)-(1-benzyl-7-chloro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methanol(2000 mg, 6.93 mmol) and Et₃N (1.931 mL, 13.85 mmol) in dry DCM (20 mL)at 0° C. was added methanesulfonyl chloride (2500 mg, 21.82 mmol). Thereaction mixture was stirred at 20° C. for 10 hours, then quenched withwater (20 mL). The biphasic mixture was extracted with DCM (3×20 mL) andthe combined organic layer was dried over Na₂SO₄ and evaporated. Thecrude product was purified by column chromatography (SiO₂, petroleumether:EtOAc=20:1 to 2:1) to give the title compound as a colorless oil.¹HNMR (CDCl3, 400 MHz) δ 7.80 (1H, s), 7.34-7.38 (2H, m), 7.30 (1H, d,J=7.2 Hz), 7.19-7.21 (2H, m), 6.81 (1H, s), 4.48 (2H, s), 4.28 (1H, dd,J=10.0, 5.2 Hz), 4.16-4.21 (1H, m), 3.50-3.50 (1H, m), 3.31-3.34 (1H,m), 3.11-3.12 (1H, m), 3.00 (3H, s), 2.81-2.83 (1H, m), 2.62-2.64 (1H,m).

Step 5—Preparation of (R andS)-1-benzyl-7-chloro-3-(iodomethyl)-1,2,3,4-tetrahydro-1,5-naphthyridine

To a solution of (R andS)-(1-benzyl-7-chloro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methylmethanesulfonate (350 mg, 0.954 mmol) in acetone (10 mL) was added NaI(143 mg, 0.954 mmol). The reaction mixture was stirred at 60° C. for 10hours, then concentrated under vacuum, diluted with water (20 mL) andextracted with EtOAc (3×20 mL). The combined organic layer was driedover Na₂SO₄, evaporated and the crude product was purified by columnchromatography (petroleum ether:EtOAc=20:1 to 5:1) to give the titlecompound as a colorless oil. ¹H-NMR (CDCl₃, 400 MHz) δ 7.79 (1H, d,J=0.4 Hz), 7.35-7.39 (2H, m), 7.31 (1H, d, J=7.2 Hz), 7.21-7.23 (2H, m),6.77 (1H, s), 4.49 (2H, s), 3.52 (1H, d, J=1.2 Hz), 3.28-3.30 (2H, m),3.17-3.22 (2H, m), 3.80-3.83 (1H, m), 2.34-2.37 (1H, m).

Step 6—Preparation of (R andS)-1-benzyl-7-chloro-3-((ethylsulfonyl)methyl)-1,2,3,4-tetrahydro-1,5-naphthyridine

To a solution of (R andS)-1-benzyl-7-chloro-3-(iodomethyl)-1,2,3,4-tetrahydro-1,5-naphthyridine(550 mg, 1.380 mmol) in DMF (10 ml) at 0° C. was added sodiumethanesulfinate (481 mg, 4.14 mmol). The reaction mixture was stirred at110° C. for 1 h in the microwave, then cooled to room temperature,quenched with water (50 mL) and extracted with EtOAc (50 mL×3). Thecombined organic layer was washed with brine (30 mL×3), dried overNa₂SO₄ and concentrated under vacuum. The crude product was purified bycolumn chromatography (SiO₂, petroleum ether:EtOAc=1:3) to give thetitle compound as a brown solid. LCMS (ESI) calculated for C₁₈H₂₂ClN₂O₂S[M+H]+: 365.1, found: 365.0. ¹H-NMR (CDCl3, 400 MHz) δ 7.78 (1H, s),7.32-7.36 (2H, m), 7.27-7.29 (1H, m), 7.19-7.21 (2H, m), 6.81 (1H, d,J=1.2 Hz), 4.49 (2H, s), 3.67-3.70 (1H, m), 3.45-3.48 (1H, m), 3.20-3.24(1H, m), 2.97-3.03 (4H, m), 2.80-2.84 (1H, m), 1.39 (3H, t, J=7.6 Hz).

Step 7—Preparation of (R andS)-5-benzyl-N-(diphenylmethylene)-7-((ethylsulfonyl)methyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-amine

A mixture of (R andS)-1-benzyl-7-chloro-3-((ethylsulfonyl)methyl)-1,2,3,4-tetrahydro-1,5-naphthyridine(350 mg, 0.959 mmol) in dioxane (10 ml) was added diphenylmethanimine(209 mg, 1.151 mmol), Cs₂CO₃ (625 mg, 1.918 mmol) andchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)palladium(ii) methyl-t-butyl ether adduct (159 mg, 0.192 mmol). Thereaction mixture degassed under argon and stirred at 110° C. for 10hours, then diluted with water (20 mL) and extracted with EtOAc (20mL×3). The combined organic layer was washed with brine (10 mL×3), driedover Na₂SO₄ and concentrated under pressure. The crude product waspurified by Prep-TLC (SiO₂, petroleum ether:EtOAc=1:2) to give the titlecompound as a yellow solid. LCMS (ESI) calculated for C₃₁H₃₂N₃O₂S[M+H]+: 510.2, found: 510.2. ¹H-NMR (CDCl3, 400 MHz) δ 7.74 (1H, d,J=7.6 Hz), 7.60 (1H, d, J=7.6 Hz), 7.41-7.42 (3H, m), 7.30-7.32 (2H, m),7.23-7.24 (3H, m), 7.17-7.18 (2H, m), 6.99-7.01 (2H, m), 6.92-6.94 (2H,m), 6.20 (1H, s), 4.26 (2H, d, J=3.6 Hz), 3.54 (1H, d, J=10.4 Hz),3.29-3.32 (1H, m), 3.05-3.09 (1H, m), 2.89-2.94 (4H, m), 2.81-2.83 (1H,m), 2.66-2.71 (1H, m), 1.30 (3H, t, J=7.6 Hz).

Step 8—Preparation of (R andS)-7-((ethylsulfonyl)methyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-amine

Pd/C (146 mg, 0.137 mmol) was added to a solution of the (R andS)-5-benzyl-N-(diphenylmethylene)-7-((ethylsulfonyl)methyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-amine(140 mg, 0.275 mmol) in MeOH (20 mL). The resulting mixture was stirredunder H₂ atmosphere (50 psi) at 40° C. for 16 hours, then filtered. Thefiltrate was concentrated under vacuum to afford crude title compound asa yellow oil. LCMS (ESI) calculated for C₁₁H₁₈N₃O₂S [M+H]⁺: 256.1,found: 256.2.

Step 9—Preparation of (R)-1,1,1-trifluoro-2-methylpropan-2-yl(7-((ethylsulfonyl)methyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamateand (S)-1,1,1-trifluoro-2-methylpropan-2-yl(7-((ethylsulfonyl)methyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate

To a mixture of (R andS)-7-((ethylsulfonyl)methyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-amine(60 mg, 0.00 mmol) and 1,1,1-trifluoro-2-methylpropan-2-yl1H-imidazole-1-carboxylate (78 mg, 0.352 mmol) in DMSO (5 mL) was addedconcentrated hydrogen chloride (0.016 mL, 0.188 mmol) and the resultingreaction stirred at 80° C. for 3 hours. The reaction mixture was dilutedwith water (20 mL) and extracted with EtOAc (3×15 mL). The organic layerwas washed with brine (3×10 mL), dried over Na₂SO₄ and concentratedunder vacuum. The crude product was purified by Prep-TLC to give thetitled racemate as a yellow solid.

The above racemate was separated by SFC (Instrument: Thar SFC 350;Column: AD (250 mm*30 mm, 10 um), 10 um; Mobile phase: 40% MEOH NH₃H₂O,80 ML/MIN; Column Temp: 38° C.; Nozzle Pressure: 100 Bar Nozzle Temp:60° C.) to give both enantiomers (faster eluent, Peak 1 from Step 9;slower eluent, Peak 2 from Step 9), which have the same analytical data:LCMS (ESI) calculated for C₁₆H₂₃F₃N₃O₄S [M+H]⁺: 410.1, found: 410.1.

Step 10—Preparation of (R)-1,1,1-trifluoro-2-methylpropan-2-yl(5-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((ethylsulfonyl)methyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamateand (S)-1,1,1-trifluoro-2-methylpropan-2-yl(5-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((ethylsulfonyl)methyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate

To a mixture of (R orS)-1,1,1-trifluoro-2-methylpropan-2-yl(7-((ethylsulfonyl)methyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate(Peak 1 from Step 9, 12 mg, 0.029 mmol) in tetrahydrofuran (1.5 mL) andpyridine (1.5 mL) was added 3-chloro-1-ethyl-1H-pyrazole-4-sulfonylchloride (20.14 mg, 0.088 mmol) and DMAP (3.58 mg, 0.029 mmol). Thereaction mixture was stirred at 100° C. for 1.5 hours in a microwave,then cooled to room temperature and directly purified by Prep-HPLC toafford the titled compound (Isomer 1, Example 111A) as brown solid.

The other enantiomer (Isomer 2, Example 111B) was prepared using asimilar procedure from Peak 2 from Step 9. Both enantiomers have sameanalytical data: LCMS (ESI) calculated for C₂₁H₂₈ClF₃N₅O₆S₂ [M+H]+:602.1, found: 607.1; ¹H-NMR (Methanol-d4, 400 MHz) δ 8.83 (1H, s), 8.45(1H, s), 8.33 (1H, s), 8.01-8.02 (1H, m), 4.16 (2H, q, J=7.2 Hz),3.40-3.46 (2H, m), 3.10-3.19 (4H, m), 2.74-2.81 (2H, m), 2.53-2.55 (1H,m), 1.78 (6H, s), 1.46 (3H, t, J=6.8 Hz), 1.36 (3H, t, J=7.6 Hz).

Example 112: Preparation of(S)-3-(1-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)propanoicacid and(R)-3-(1-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)propanoicacid (Example 112A and 112B)

Step 1—Preparation of (E)-ethyl 3-(3-amino-5-chloropyridin-2-yl)acrylate

To a solution of 2,5-dichloropyridin-3-amine (5 g, 30.7 mmol) in DMF (50ml) were added ethyl acrylate (3.69 g, 36.8 mmol), DIPEA (8.04 ml, 46.0mmol), Pd(OAc)₂ (0.689 g, 3.07 mmol), Bu₄NBr (0.989 g, 3.07 mmol) and(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (1.910 g, 3.07mmol). The reaction mixture was heated to 140° C. and stirred for 30hours. The reaction mixture was cooled to room temperature, and thenpoured into water (200 mL), extracted with EtOAc (200 mL×3), thecombined organic layers were washed by brine (200 mL×3), dried overanhydrous Na₂SO₄ and evaporated under vacuum. The crude product waspurified by silica gel column chromatography (EtOAc:petroleumether=0-30%) to afford (E)-ethyl3-(3-amino-5-chloropyridin-2-yl)acrylate as a yellow solid. LCMS (ESI)calculated for C₁₀H₁₂ClN₂O₂[M+H]⁺: 227.1, found: 227.2.

Step 2—Preparation of ethyl 3-(3-amino-5-chloropyridin-2-yl)propanoate

Pd/C (2.35 g, 2.21 mmol) was added to a solution of the (E)-ethyl3-(3-amino-5-chloropyridin-2-yl)acrylate (2.5 g, 11.03 mmol) in MeOH (10ml). The mixture was stirred under H₂ atmosphere (1 atm) at 0° C. for 2h and then filtered. The filtrate was concentrated under vacuum and thecrude product was purified by column chromatography on silica gel(EtOAc:petroleum ether=0-30%) to afford ethyl3-(3-amino-5-chloropyridin-2-yl)propanoate as a yellow solid. LCMS (ESI)calculated for C₁₀H₁₄ClN₂O₂ [M+H]⁺: 229.1, found: 229.1.

Step 3—Preparation of 7-chloro-3,4-dihydro-1,5-naphthyridin-2(1H)-one

AcOH (1.502 ml, 26.2 mmol) was added to a solution of the ethyl3-(3-amino-5-chloropyridin-2-yl)propanoate (2 g, 8.75 mmol) intetrahydrofuran (50 ml). The mixture was heated to 60° C. and stirredfor 2 hours. The reaction mixture was concentrated under vacuum and thecrude product was purified by column chromatography on silica gel(EtOAc:petroleum ether=0-30%) to afford7-chloro-3,4-dihydro-1,5-naphthyridin-2(1H)-one as a yellow solid. LCMS(ESI) calculated for C₈H₈ClN₂O [M+H]⁺: 183.0, found: 183.1.

Step 4—Preparation of1-benzyl-7-chloro-3,4-dihydro-1,5-naphthyridin-2(1H)-one

At 0° C., to a solution of7-chloro-3,4-dihydro-1,5-naphthyridin-2(1H)-one (2 g, 10.95 mmol) inN,N-dimethylformamide (20 mL) was added Cs₂CO₃ (5.35 g, 16.43 mmol),followed by (bromomethyl)benzene (2.061 g, 12.05 mmol). The reactionmixture was stirred at room temperature for 1 hour. The reaction mixturewas poured into water (50 mL), then extracted with EtOAc (50 ml×3). Thecombined organic layers were washed with brine (50 ml×3), dried overanhydrous Na₂SO₄ and concentrated under vacuum. The crude product waspurified by column chromatography on silica gel (EtOAc:petroleumether=0-30%) to afford1-benzyl-7-chloro-3,4-dihydro-1,5-naphthyridin-2(1H)-one as a yellowsolid. LCMS (ESI) calculated for C₁₅H₁₄ClN₂O [M+H]⁺: 273.1, found:273.2.

Step 5—Preparation of (R and S)-methyl1-benzyl-7-chloro-2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridine-3-carboxylate

At −78° C., to a solution of1-benzyl-7-chloro-3,4-dihydro-1,5-naphthyridin-2(1H)-one (2 g, 7.33mmol) in dry tetrahydrofuran (50 mL) was added LHMDS (8.80 mL, 8.80mmol), the mixture was stirred at −78° C. for 30 minutes, then methylcarbonochloridate (0.832 g, 8.80 mmol) was added. The reaction mixturewas stirred at −78° C. for 1 hour and quenched with saturated solutionof NH₄Cl (20 mL). The aqueous layer was extracted with EtOAc (50 mL×3)and the combined organic layers were washed with brine (50 mL×3), driedover anhydrous Na₂SO₄ and concentrated under vacuum. The crude productwas purified by flash chromatography on silica gel (EtOAc:petroleumether=0-30%) to afford (R and S)-methyl1-benzyl-7-chloro-2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridine-3-carboxylateas a yellow solid. LCMS (ESI) calculated for C₁₇H₁₆ClN₂O₃[M+H]⁺: 331.1,found: 331.2.

Step 6—Preparation of (R andS)-(1-benzyl-7-chloro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methanol

At 0° C., to a solution of (R and S)-methyl1-benzyl-7-chloro-2-oxo-1,2,3,4-tetrahydro-1,5-naphthyridine-3-carboxylate(1.7 g, 5.14 mmol) in dry tetrahydrofuran (50 ml) was added BH₃—SMe₂(2.440 mL, 25.7 mmol) and the reaction mixture was stirred at 60° C. for2 hours. The reaction was quenched with MeOH (10 mL), then concentratedunder vacuum. The crude product was purified by column chromatography onsilica gel (EtOAc:petroleum ether=0-30%) to afford the title compound asa yellow solid. LCMS (ESI) calculated for C₁₆H₁₈ClN₂O [M+H]⁺: 289.1,found: 289.2.

Step 7—Preparation of (S andR)-1-benzyl-3-(bromomethyl)-7-chloro-1,2,3,4-tetrahydro-1,5-naphthyridine

To a solution of (R andS)-(1-benzyl-7-chloro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methanol(500 mg, 1.731 mmol) and CBr₄ (1263 mg, 3.81 mmol) in THF (20 ml) wasadded Ph₃P (1045 mg, 3.98 mmol) portionwise. The reaction mixture wasstirred at 60° C. for 16 hours, then concentrated in vacuo. The crudeproduct was purified by column chromatography on silica gel(EtOAc:petroleum ether=0-20%) to give the title compound as a yellowsolid. LCMS (ESI) calculated for C₁₆H₁₇BrClN₂ [M+H]⁺: 351.0, found:351.1.

Step 8—Preparation of (R and S)-diethyl2-((1-benzyl-7-chloro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)malonate

To a solution of (S andR)-1-benzyl-3-(bromomethyl)-7-chloro-1,2,3,4-tetrahydro-1,5-naphthyridine(1 g, 2.84 mmol) and diethyl malonate (0.592 g, 3.70 mmol) inN,N-dimethylformamide (10 ml) was added K₂CO₃ (0.786 g, 5.69 mmol). Thereaction mixture was stirred at 100° C. for 16 hours, then quenched withwater (50 ml) and 1N HCl (5 ml). The aqueous layer was extracted withEtOAc (20 mL×3). The combined organic phase was washed with brine (20ml×3), dried over Na₂SO₄, and concentrated in vacuo. The residue waspurified by column chromatography (petroleum ether:EtOAc=100:1 to 10:1)to give the title compound as a yellow solid. LCMS (ESI) calculated forC₂₃H₂₈ClN₂O₄ [M+H]⁺: 431.2, found: 431.2.

Step 9—Preparation of (R and S)-ethyl3-(1-benzyl-7-chloro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)propanoate

A mixture of (R and S)-diethyl2-((1-benzyl-7-chloro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)methyl)malonate(500 mg, 1.160 mmol) in DMSO (10 ml) was added LiCl (246 mg, 5.80 mmol).The reaction mixture was stirred at 170° C. for 10 h, then poured intowater (100 mL) and extracted with EtOAc (50 mL×3). The organic layer waswashed with brine (50 mL×3), dried over Na₂SO₄ and concentrated invacuo. The crude product was purified by column chromatography(EtOAc:petroleum ether=0-20%) to give the title compound as a yellowsolid. LCMS (ESI) calculated for C₂₀H₂₄ClN₂O₂ [M+H]⁺: 359.1, found:359.1.

Step 10—Preparation of (R and S)-ethyl3-(1-benzyl-7-((diphenylmethylene)amino)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)propanoate

A mixture of (R and S)-ethyl3-(1-benzyl-7-chloro-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)propanoate(100 mg, 0.279 mmol) in toluene (10 mL) was added diphenylmethanimine(60.6 mg, 0.334 mmol), Pd₂(dba)₃ (25.5 mg, 0.028 mmol) and K₃PO₄ (1509mg, 7.11 mmol). The reaction mixture was stirred at 100° C. for 16 h,then quenched with water (10 mL) and extracted with EtOAc (10 mL×3). Theorganic layer was washed with brine (10 mL×3), dried over Na₂SO₄ andconcentrated in vacuo. The crude product was purified by columnchromatography on silica gel (EtOAc:petroleum ether=0-30%) to give thetitle compound as a yellow solid. LCMS (ESI) calculated for C₃₃H₃₄N₃O₂[M+H]⁺: 504.3, found: 504.3.

Step 11—Preparation of (R and S)-ethyl3-(7-amino-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)propanoate

Pd/C (21.13 mg, 0.020 mmol, w/w %=10%) was added to a solution of (R andS)-ethyl3-(1-benzyl-7-((diphenylmethylene)amino)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)propanoate(50 mg, 0.099 mmol) in EtOH (10 mL). The mixture was stirred under H₂atmosphere (50 psi) at 18° C. for 16 h, then filtered. The filtrate wasconcentrated under vacuum to afford the crude title compound as a yellowsolid, which was used without further purification. LCMS (ESI)calculated for C₁₃H₂₀N₃O₂ [M+H]⁺: 250.2, found: 250.2.

Step 12—Preparation of (S)-ethyl3-(7-(3,3,3-trifluoro-2,2-dimethylpropanamido)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)propanoateand (R)-ethyl3-(7-(3,3,3-trifluoro-2,2-dimethylpropanamido)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)propanoate

A mixture of (R and S)-ethyl3-(7-amino-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)propanoate (100 mg,0.401 mmol) and 1,1,1-trifluoro-2-methylpropan-2-yl1H-imidazole-1-carboxylate (107 mg, 0.481 mmol) in DMSO (5 ml) wastreated with concentrated HCl (19.76 mg, 0.201 mmol) and stirred at 80°C. for 5 hours. The reaction mixture was diluted with water (20 ml) andextracted with EtOAc (20 ml×3). The organic layer was washed with brine(10 mL×3), dried over Na₂SO₄ and concentrated in vacuo. The crudeproduct was purified by column chromatography on silica gel(EtOAc:petroleum ether=0-30%) to give an (R)- and (S)-mixture of ethyl3-(7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)propanoateas a yellow solid. LCMS (ESI) calculated for C₁₈H₂₅F₃N₃O₄ [M+H]⁺: 404,found: 404.

The mixture of enantiomers (Isomer 1 and Isomer 2) was resolved by SFC(Instrument: Thar SFC 350 Column: AD 250 mm*30 mm, 10 um Mobile phase:A: Supercritical CO₂, B: EtOH (0.1% NH₃H₂O), A:B=80:20 at 60 ml/min;Column Temp: 38° C.; Nozzle Pressure: 100 Bar; Nozzle Temp: 60° C.;Evaporator Temp: 25° C.; Trimmer Temp: 25° C.; Wavelength: 220 nm) toafford (R)-ethyl3-(7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)propanoateand (S)-ethyl3-(7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)propanoateas a yellow solid LCMS (ESI) calculated for C₁₈H₂₅F₃N₃O₄ [M+H]⁺: 404,found: 404.

Step 13—Preparation of (S)-ethyl3-(1-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)propanoateand (R)-ethyl3-(1-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)propanoate

To a solution of (S or R)-ethyl3-(7-(3,3,3-trifluoro-2,2-dimethylpropanamido)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)propanoate(Isomer 1 from Step 12, 50 mg, 0.124 mmol) in pyridine (2 mL) and THF (2mL) was added 3-chloro-1-ethyl-1H-pyrazole-4-sulfonyl chloride (34.1 mg,0.149 mmol). The reaction was stirred at 60° C. for 3 h, then treatedwith 1M HCl aqueous solution (pH ˜4) and extracted with EtOAc (10 mL×3).The combined organic layers were dried over anhydrous Na₂SO₄, andconcentrated. The title compound (Isomer 1 from Step 13) was obtained byprep-TLC (SiO₂, petroleum ether:EtOAc=2:1) as a yellow solid.

The other enantiomer (Isomer 2 from Step 13) was prepared using asimilar procedure as described above. Both enantiomers have the sameanalytical data: LCMS (ESI) calculated for C₂₃H₃₀ClF₃N₅O₆S [M+H]⁺: 596,found: 596.

Step 14—Preparation of(S)-3-(1-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)propanoicacid and(R)-3-(1-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)propanoicAcid

To a solution (S)-ethyl3-(1-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)propanoate(Isomer 1 from Step 13, 30 mg, 0.050 mmol) in acetonitrile (2 mL) andwater (2 mL) was added lithium hydroxide (1.205 mg, 0.050 mmol) and thereaction was warmed to 20° C. for 1 h. The reaction mixture wasevaporated under vacuum and the residue purified by prep-HPLC(MeCN/water using TFA buffer) to afford the title compound (R orS)-3-(1-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl)propanoicacid (Isomer 1, Example 112A) as a white solid.

The other enantiomer (Isomer 2, Example 112B) was prepared using asimilar procedure from Isomer 2 from Step 13. Both enantiomers have thesame analytical data: LCMS (ESI) calculated for C₂₁H₂₆ClF₃N₅O₆S [M+H]⁺:568, found: 568. ¹HNMR (400 MHz, CDCl₃) δ 8.89 (1H, s), 8.79 (1H, s),8.59 (1H, s), 8.24 (1H, s), 4.31 (1H, d, J=12.0 Hz), 4.13 (1H, q, J=7.0Hz), 3.45-3.50 (2H, m), 3.29 (1H, d, J=15.2 Hz), 2.76 (2H, m), 2.49 (1H,br s), 2.15 (1H, br s), 1.74-1.79 (7H, m), 1.50 (1H, d, J=7.2 Hz).

Example 113—Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl(14(4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamate(Example 113)

Step 1—Preparation of 1,2,3,4-tetrahydroquinolin-7-amine

7-Nitro-1,2,3,4-tetrahydroquinoline (2 g, 11.22 mmol) and Pd/C (1.2 g)in EtOH (20 mL) were stirred under H₂ at 25° C. for 1 h, then filtrated.The filtrate was concentrated to obtain the product as black oil. LCMS(ESI) calculated for C₉H₁₃N₂ [M+H]⁺: 149, found: 149 ¹H NMR (CDCl₃ 400MHz,) δ 6.68-6.75 (1H, m), 5.99 (1H, dd, J=2.0, 7.8 Hz), 5.78-5.86 (1H,m), 3.21-3.25 (2H, m), 2.63 (2H, t, J=6.3 Hz, 2H), 1.85-1.92 (2H, m).

Step 2—Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl(1,2,3,4-tetrahydroquinolin-6-yl)carbamate

A solution of 1,2,3,4-tetrahydroquinolin-6-amine (1.2 g, 8.10 mmol) and3-methyl-1-(((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)-1H-imidazol-3-iumiodide (1.921 g, 8.10 mmol) in 15 mL of DMSO was stirred at 25° C. for 2h, then quenched with H₂O and extracted 3× with EtOAc. The combinedorganic layers were dried and concentrated. The crude product waspurified by column chromatography (petroleum ether:EtOAc=10:1) to give1,1,1-trifluoro-2-methylpropan-2-yl(1,2,3,4-tetrahydroquinolin-6-yl)carbamate as yellow slid. LCMS (ESI)calculated for C₁₄H₁₈F₃N₂O₂ [M+H]⁺: 303, found: 303. ¹H NMR (CDCl₃ 400MHz,) δ 6.82 (1H, d, J=8.2 Hz), 6.64 (1H, br s), 6.50 (1H, brs), 6.40(1H, d, J=7.4 Hz), 3.22-3.28 (2H, m), 2.67 (2H, t, J=6.1 Hz, 2H), 1.89(2H, d, J=5.8 Hz, 2H), 1.72 (6H, s).

Step 3—Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl(1-((4-fluorophenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamate

To a solution of 1,1,1-trifluoro-2-methylpropan-2-yl(1,2,3,4-tetrahydroquinolin-7-yl)carbamate (200 mg, 0.662 mmol) andpyridine (10.5 mg, 0.13 mmol) in THF (2 mL) was added4-fluorobenzene-1-sulfonyl chloride (28 mg, 0.14 mmol) at roomtemperature. The reaction mixture was stirred at 80° C. overnight, thencooled and extracted with water and EtOAc. The combined organic layerswere washed with brine, dried over Na₂SO₄, and concentrated in vacuo.The crude product was purified by prep-HPLC (MeCN/water using TFAbuffer) to give the title compound as colorless oil. LCMS (ESI)calculated for C₂₀H₂₁F₄N₂O₄S [M+H]⁺: 461, found: 461. ¹H NMR (CD₃OD, 400MHz) δ 7.86 (brs, 1H), 7.68-7.76 (m, 2H), 7.12-7.26 (m, 3H), 6.94 (d,J=8.2 Hz, 1H), 3.77-3.85 (m, 2H), 2.41 (t, J=6.46 Hz, 2H), 1.76 (s, 6H),1.60-1.69 (m, 2H).

Example 114—Preparation of Additional 1,2,3,4-tetrahydroquinolines

The compounds in Table 33 below were prepared based on the experimentalprocedures described in Example 113 and elsewhere in the detaileddescription, and can be achieved by one of skill in the art in light ofthe present disclosure.

TABLE 33 Ex. Observed No. Structure Name m/z 114A

2,2,2-trifluoro-1,1- dimethylethyl {l-[(3- chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl]-1,2,3,4- tetrahydroquinolin-7- yl}carbamate 495 (M + H)+114B

2,2,2-trifluoro-1,1- dimethylethyl (1-{[1-ethyl- 3-(2-hydroxyethoxy)-1H-pyrazol-4-yl]sulfonyl}- 1,2,3,4-tetrahydroquinolin- 7-yl)carbamate 521(M + H)+ 114C

2,2,2-trifluoro-1,1- dimethylethyl {1-[(3- ethoxy-1-ethyl-1H-pyrazol-4-yl)sulfonyl]-1,2,3,4- tetrahydroquinolin-7- yl}carbamate 505 (M + H)+114D

2,2,2-trifluoro-1,1- dimethylethyl (1-{[2- (trifluoromethyl)pyridin-4-yl]sulfonyl}-1,2,3,4- tetrahydroquinolin-7- yl)carbamate 512 (M + H)+

Example 115—Preparation of (R or S) and (S orR)-1,1,1-trifluoro-2-methylpropan-2-yl(3-(acetamidomethyl)-1-((4-fluoro-3-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamate(Examples 115A and 115B)

Step 1—Preparation of (2-amino-4-nitrophenyl)methanol

To a solution of 2-amino-4-nitrobenzoic acid (10 g, 54.9 mmol) in THF(150 mL), which was stirred in a 500 mL of sealed tube, was slowly addedBH₃.DMS (15.64 mL, 165 mmol) dropwise at 0° C. under N₂. The resultingmixture was stirred at 90° C. for 4 h, then cooled to 0° C. and treateddropwise with MeOH (60 mL). The resulting suspension was concentrated toafford the crude titled compound as a yellow solid, which was directlyused in the next step without further purification. LCMS (ESI)calculated for C₇H₉N₂O₃ [M+H]⁺: 169 found: 169. ¹HNMR (CDCl₃, 400 MHz) δ7.54 (1H, s), 7.46 (1H, dd, J=8.0, 1.6 Hz), 7.31 (1H, d, J=8.4 Hz), 4.60(2H, s).

Step 2—Preparation of 2-amino-4-nitrobenzaldehyde

A mixture of (2-amino-4-nitrophenyl)methanol (9 g, 53.5 mmol) andmanganese (IV) oxide (93 g, 1070 mmol) in DCM (150 mL) and hexane (150mL) was stirred at 20° C. for 1 h. The suspension was filtered andwashed with DCM. The filtrate was concentrated in vacuo to give thecrude titled product as a yellow solid, which was directly used in nextstep without further purification. ¹H-NMR (CDCl₃, 400 MHz) δ 9.95 (1H,s), 7.63 (1H, d, J=8.8 Hz), 7.47 (2H, d, J=6.0 Hz), 6.38 (2H, br s).

Step 3—Preparation of methyl7-nitro-2-oxo-1,2-dihydroquinoline-3-carboxylate

A mixture of 2-amino-4-nitrobenzaldehyde (6.6 g, 39.7 mmol), potassiumacetate (0.390 g, 3.97 mmol), dimethyl malonate (6.30 g, 47.7 mmol), anddiacetoxycopper (0.361 g, 1.986 mmol) in HOAc (60 mL) was stirred at110° C. for 48 h. Most of the solvent was removed in vacuo and theresulting precipitate was collected by filtration, washed with EtOAc anddried in vacuo to give the titled compound as a yellow solid. LCMS (ESI)calculated for C₁₁H₉N₂O₅ [M+H]⁺: 249, found: 249. ¹H-NMR (DMSO-d6, 400MHz) δ 12.44 (1H, s), 8.60 (1H, s), 8.07 (2H, s), 7.97 (1H, s), 3.80(3H, s).

Step 4—Preparation of (R andS)-(7-nitro-1,2,3,4-tetrahydroquinolin-3-yl)methanol

To a solution of methyl 7-nitro-2-oxo-1,2-dihydroquinoline-3-carboxylate(3 g, 12.05 mmol) in THF (200 mL) was added LiBH₄ (1.27 g, 60.24 mmol).The mixture was stirred at 40° C. for 18 h, then quenched by the carefuladdition of saturated NH₄Cl aqueous solution (20 mL). The biphasicmixture was stirred at 20° C. for 30 min, then extracted with EtOAc (200mL×3). The combined organic phases were washed with brine (600 mL×2),dried over Na₂SO₄, filtered and concentrated in vacuo. Purification bysilica gel column chromatography (petroleum ether/EtOAc=3:1 to 1:3)afforded the titled compound as a red solid. LCMS (ESI) calculated forC₁₀H₁₃N₂O₃ [M+H]⁺: 209, found: 209; ¹H-NMR (Methanol-d4, 400 MHz) δ 7.30(2H, s), 7.05 (1H, d, J=7.6), 3.41-3.57 (3H, m), 3.05 (1H, t, J=10.4Hz), 2.86 (1H, d, J=15.2 Hz), 2.54-2.58 (1H, m), 2.06 (1H, br s).

Step 5—Preparation of (R andS)-2-((7-nitro-1,2,3,4-tetrahydroquinolin-3-yl)methyl)isoindoline-1,3-dione

To a solution of (7-nitro-1,2,3,4-tetrahydroquinolin-3-yl)methanol (450mg, 2.16 mmol) in THF (20 mL) was added DEAD (450 mg, 2.60 mmol), Ph₃P(682 mg, 2.60 mmol), and isoindoline-1,3-dione (383 mg, 2.60 mmol). Thereaction was stirred at 20° C. for 16 h under N₂, then partitionedbetween EtOAc (20 mL) and H₂O (20 mL). The separated organic layer waswashed with brine (30 mL×2) and dried over Na₂SO₄. The solvents wereremoved and the crude product was purified by silica gel columnchromatography (petroleum ether/EtOAc=10:1 to 1:1) to afford the titledcompound as a yellow solid. LCMS (ESI) calculated for C₁₈H₁₆N₃O₄ [M+H]⁺:338, found: 338; ¹H-NMR (Methanol-d4, 400 MHz) δ 7.79-7.85 (4H, m),7.27-7.34 (2H, m), 7.02-7.04 (1H, m), 3.70 (1H, d, J=7.2 Hz), 3.07-3.11(2H, m), 2.83-2.91 (1H, m), 2.58-2.61 (1H, m), 2.36 (1H, br s).

Step 6—Preparation of (R)-tert-butyl(3-((1,3-dioxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamateand (S)-tert-butyl(3-((1,3-dioxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamate

To a solution of (R andS)-2-((7-nitro-1,2,3,4-tetrahydroquinolin-3-yl)methyl)isoindoline-1,3-dione(550 mg, 1.63 mmol) in EtOAc (20 mL) was added di-tert-butyl dicarbonate(1.07 g, 4.90 mmol) and Pd/C (55 mg, 10%). The resulting mixture wasstirred at 20° C. under H₂ balloon for 18 h, then filtered, the filtrateconcentrated under the reduced pressure and purified by silica gelcolumn chromatography (petroleum ether/EtOAc=10:1 to 1:1) to afford thetitle compound racemate as a light yellow solid.

The racemic mixture was resolved by chiral SFC method (Pak AS, 10 μm,Daicel Chemical Industries, Ltd 250×30 mm I.D.; Mobile phase: A:Supercritical CO₂, B:EtOH (contained 0.1% NH₃H₂O), A:B=50:50 at 80mL/min) to afford the faster eluent (Peak 1 from Step 6) and the slowereluent (Peak 2 from Step 6) both as yellow oils. Both enantiomers havethe same analytical data: LCMS (ESI) calculated for C₂₃H₂₆N₃O₄ [M+H]⁺:408, found: 408; ¹H-NMR (CDCl₃, 400 MHz) δ 7.84-7.86 (2H, m), 7.72-7.74(2H, m), 6.77-6.83 (2H, m), 6.38-6.40 (2H, m), 3.70 (2H, d, J=6.4 Hz),3.30 (1H, d, J=10.8 Hz), 3.05 (1H, t, J=10.0 Hz), 2.79 (1H, dd, J=12.0,4.0 Hz), 2.50-2.57 (1H, m), 1.49 (9H, s).

Step 7—Preparation of(R)-tert-butyl(3-((1,3-dioxoisoindolin-2-yl)methyl)-1-((4-fluoro-3-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamateand(S)-tert-butyl(3-((1,3-dioxoisoindolin-2-yl)methyl)-1-((4-fluoro-3-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamate

To a solution of (R or S)-tert-butyl(3-((1,3-dioxoisoindolin-2-yl)methyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamate(Peak 1 from Step 6, 120 mg, 0.290 mmol) in THF (3 mL) were addedpyridine (3 mL) and 4-fluoro-3-methoxybenzene-1-sulfonyl chloride (132mg, 0.590 mmol) at 20° C. under N₂. The resulting mixture was stirred at50° C. for 18 h, then poured into water. The aqueous layer was extractedwith ethyl acetate (20 mL×3) and the combined organic layers washed withbrine (30 mL×2), dried over sodium sulfate and concentrated. The crudeproduct was purified by prep-TLC (petroleum ether/EtOAc=1:1) to affordthe titled compound (Peak 1 from Step 7) as a yellow oil.

The other enantiomer (Peak 2 from Step 7) was prepared using a similarprocedure as described above from Peak 2 from Step 6. Both enantiomershave the same analytical data: LCMS (ESI) calculated for C₂₆H₂₃FN₃O₇S[M+H-tBu]⁺: 540, found: 540.1; ¹H-NMR (CDCl₃, 400 MHz) δ 7.86-7.89 (2H,m), 7.76-7.78 (2H, m), 7.67 (1H, s), 7.57-7.60 (1H, m), 3.73 (3H, s),3.56 (2H, d, J=6.8 Hz), 3.17 (1H, t, J=12.4 Hz), 2.55 (1H, dd, J=16.8,5.2 Hz), 2.17-2.25 (2H, m), 2.01-2.05 (1H, m), 1.49 (9H, s).

Step 8—Preparation of (R)-tert-butyl(3-(aminomethyl)-1-((4-fluoro-3-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamateand (S)-tert-butyl(3-(aminomethyl)-1-((4-fluoro-3-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamate

A solution of (R or S)-tert-butyl tert-butyl(3-((1,3-dioxoisoindolin-2-yl)methyl)-1-((4-fluoro-3-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamate(Peak 1 from Step 7, 60 mg, 0.10 mmol) in EtOH (15 mL) was treated withN₂H₄—H₂O (0.5 mL) for 2 h at 85° C., then cooled to room temperature andfiltered. The filtrate was concentrated, purified by silica gelchromatography (EtOAc/MeOH=5:1) to afford the title compound as a lightyellow solid.

The other enantiomer (Peak 2 from Step 8) was prepared using a similarprocedure as described above from Peak 2 from Step 7. Both enantiomershave the same analytical data: LCMS (ESI) calculated for C₂₂H₂₉FN₃O₅S[M+H]⁺: 466, found: 466; ¹H-NMR (CDCl₃, 400 MHz) δ 7.72 (1H, s), 7.47(1H, s), 7.32 (1H, d, J=6.4 Hz), 7.11 (1H, t, J=8.8 Hz), 6.86 (1H, dd,J=25.2, 8.0 Hz), 4.32 (1H, d, J=10.8 Hz), 3.78 (3H, s), 3.48 (2H, s),3.37 (1H, br s), 3.09 (2H, br s), 2.69 (1H, d, J=14.0 Hz), 2.46 (1H, brs), 2.27 (1H, br s), 1.49 (9H, s).

Step 9—Preparation of(R)-tert-butyl(3-(acetamidomethyl)-1-((4-fluoro-3-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamateand(S)-tert-butyl(3-(acetamidomethyl)-1-((4-fluoro-3-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamate

To a solution of (R or S)-tert-butyl(3-(aminomethyl)-1-((4-fluoro-3-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamate(Peak 1 from Step 8, 40 mg, 0.086 mmol) in 3 mL of methylene chloride isfirst added TEA (0.036 mL, 0.258 mmol) and then slowly treated withacetyl chloride (10.12 mg, 0.129 mmol). The reaction mixture is stirredat 20° C. for two hours, then quenched with water (0.5 mL). Theseparated organic layer was dried over Na₂SO₄, filtered andconcentrated. The crude product was purified by prep-TLC (petroleumether/EtOAc=1:2) to afford the title compound (Peak 1 from Step 9) as alight yellow solid.

The other enantiomer (Peak 2 from Step 9) was prepared using a similarprocedure as described above from Peak 2 from Step 8. Both enantiomershave the same analytical data: LCMS (ESI) calculated for C₂₄H₃₁FN₃O₆S[M+H]⁺: 508.2, found: 508.2; ¹H-NMR (CDCl₃, 400 MHz) δ 7.73 (1H, s),7.33-7.35 (2H, m), 7.15-7.18 (1H, m), 7.06-7.08 (1H, m), 6.95 (1H, d,J=8.8 Hz), 6.61 (1H, br s), 6.06 (1H, br s), 3.91 (1H, dd, J=13.2, 2.8Hz), 3.85 (3H, s), 3.47-3.51 (1H, m), 3.34-3.36 (1H, m), 3.05-3.09 (1H,m), 2.66 (1H, dd, J=16.4, 6.0 Hz), 2.22-2.27 (1H, m), 2.02 (3H, s), 1.51(9H, s).

Step 10—Preparation of(R)—N-((7-amino-1-((4-fluoro-3-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)acetamideand(S)—N-((7-amino-1-((4-fluoro-3-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)acetamide

To a solution of (R or S)-tert-butyl(3-(acetamidomethyl)-1-((4-fluoro-3-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamate(Peak 1 from Step 9, 30 mg, 0.059 mmol) in EtOAc (1 mL) was added HCl (2mL, 4 M in EtOAc). The reaction was stirred at 20° C. for 2 h, thenconcentrated and purified by prep-TLC (petroleum ether/EtOAc=1:2) toafford the titled compound (Peak 1 from Step 10) as a light yellowsolid.

The other enantiomer (Peak 2 from Step 10) was prepared using a similarprocedure as described above from Peak 2 from Step 9. Both enantiomershave the same analytical data: LCMS (ESI) calculated for C₁₉H₂₃FN₃O₄S[M+H]⁺: 408.1, found: 408.1; ¹H-NMR (CDCl₃, 400 MHz) δ 7.26-7.28 (1H,m), 7.13-7.16 (2H, m), 7.06 (1H, d, J=2.4 Hz), 6.81 (1H, d, J=8.0 Hz),6.46 (1H, d, J=2.0 Hz), 5.76 (1H, br s), 4.00 (1H, dd, J=13.6, 4.0 Hz),3.78 (3H, s), 3.26-3.35 (2H, m), 3.02-3.08 (1H, m), 2.52 (1H, dd,J=16.0, 6.4 Hz), 2.66 (1H, dd, J=16.4, 6.0 Hz), 2.08-2.18 (1H, m), 2.01(3H, s).

Step 11—Preparation of (R)-1,1,1-trifluoro-2-methylpropan-2-yl(3-(acetamidomethyl)-1-((4-fluoro-3-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamateand (S)-1,1,1-trifluoro-2-methylpropan-2-yl(3-(acetamidomethyl)-1-((4-fluoro-3-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamate

To a solution of (R orS)—N-((7-amino-1-((4-fluoro-3-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-3-yl)methyl)acetamide(Peak 1 from Step 10, 20 mg, 0.049 mmol) in DMSO (5 mL) was added3-methyl-1-(((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)-1H-imidazol-3-iumiodide (24.3 mg, 0.098 mmol). The resulting mixture was stirred at 20°C. for 1 h, then extracted with EtOAc (5 mL×3), washed with brine (5mL×2), dried over Na₂SO₄ and purified by prep-HPLC to afford the titlecompound (Peak 1 from Step 11, Example 115A) as a white solid.

The other enantiomer (Peak 2 from Step 11, Example 115B) was preparedusing a similar procedure as described above from Peak 2 from Step 10.Both enantiomers have the same analytical data: LCMS (ESI) calculatedfor C₂₄H₂₈F₄N₃O₆S [M+H]⁺: 562.1, found: 562.1; ¹H-NMR (CDCl₃, 400 MHz) δ7.75 (1H, s), 7.39 (2H, br s), 7.19 (1H, t, J=10.4 Hz), 6.68 (1H, s),6.26 (1H, s), 3.89 (3H, s), 3.82-3.86 (1H, m), 3.64-3.67 (1H, m),3.44-3.48 (1H, m), 3.09-3.11 (1H, m), 2.73-2.78 (2H, m), 2.33 (1H, dd,J=16.8, 6.4 Hz), 2.10 (3H, s), 1.75 (6H, d, J=4.4 Hz).

Example 116—Preparation of(R)-3-(1-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydroquinolin-3-yl)propanoicacid and(S)-3-(1-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydroquinolin-3-yl)propanoicacid (Examples 116A and 116B)

Step 1—Preparation of 7-nitroquinoline

To a solution of 7-nitro-1,2,3,4-tetrahydroquinoline (8 g, 44.9 mmol) inDCM (400 mL) was added4,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile (21 g, 93mmol). The mixture was stirred for 1 hour at 60° C. The reaction mixturewas poured into water (500 mL), extracted with dichloromethane (200mL×3). The combined organic phase was dried over Na₂SO₄ and concentratedin vacuo. The residue was purified by flash silica gel chromatography(SiO₂, PE:EtOAc=5:1 to 1:1) to give 7-nitroquinoline as a yellow solid.

Step 2—Preparation of 3-bromo-7-nitroquinoline

To a solution of 7-nitroquinoline (3 g, 17.23 mmol) in AcOH (50 mL) wasadded 1-bromopyrrolidine-2,5-dione (4.4 g, 24.72 mmol) under N₂. Themixture was stirred for 4 hours at 140° C. The reaction mixture waspoured into water (200 mL), extracted with ethyl acetate (100 mL×3). Thecombined organic phase was dried over Na₂SO₄ and concentrated in vacuo.The residue was purified by flash silica gel chromatography (SiO₂,petroleum ether:EtOAc=100:1 to 5:1) to give 3-bromo-7-nitroquinoline asa yellow solid.

Step 3—Preparation of (E)-methyl 3-(7-nitroquinolin-3-yl)acrylate

To a solution of 3-bromo-7-nitroquinoline (2 g, 7.90 mmol), potassiumphosphate (3.36 g, 15.81 mmol), methyl acrylate (0.680 g, 7.90 mmol) inDMA (15 mL) and water (3 mL) was added Pd(PPh₃)₄ (0.539 g, 0.790 mmol)under N₂. The mixture was stirred at 90° C. for 16 hours under N₂. Thereaction was then diluted with EtOAc (20 mL) and water (50 mL). Theaqueous layer was extracted with EtOAc (3×20 mL). The combined organicphase was dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by flash silica gel chromatography (SiO₂, petroleumether:EtOAc=20:1 to 3:1) to give (E)-methyl3-(7-nitroquinolin-3-yl)acrylate as a black solid. ¹H NMR (400 MHz,CDCl₃) δ 3.63 (s, 3H), 6.57 (d, J=16.4 Hz, 1H), 7.63 (d, J=16.4 Hz, 1H),7.86 (d, J=9.0 Hz, 1H), 8.12 (s, 1H), 8.21 (s, 1H), 8.74 (br. s., 1H),8.98-9.05 (m, 1H), 9.02 (s, 1H).

Step 4—Preparation (S and R)-tert-butyl7-((tert-butoxycarbonyl)amino)-3-(3-methoxy-3-oxopropyl)-3,4-dihydroquinoline-1(2H)-carboxylate

To a solution of (E)-methyl 3-(7-nitroquinolin-3-yl)acrylate (2 g, 7.75mmol), di-tert-butyl dicarbonate (3.38 g, 15.49 mmol) in MeOH (300 mL)was added Pd/C (0.412 g, 3.87 mmol) under N₂. The suspension wasdegassed under vacuum and purged with H₂ several times. The mixture wasstirred under H₂ (50 psi) at 25° C. for 16 hours. The suspension wasfiltered through a pad of CELITE and the filter cake was washed withMeOH (100 mL×3). The combined filtrates were concentrated to dryness.The residue was purified by flash silica gel chromatography (SiO₂,petroleum ether:EtOAc=100:1 to 5:1) to give the title compound as abrown oil.

Step 5—Preparation of (S and R)-methyl3-(7-amino-1,2,3,4-tetrahydroquinolin-3-yl)propanoate

To a mixture of (S and R)-tert-butyl7-((tert-butoxycarbonyl)amino)-3-(3-methoxy-3-oxopropyl)-3,4-dihydroquinoline-1(2H)-carboxylate(1.2 g, 2.76 mmol) in DCM (10.0 mL) was added dropwise TFA (5.0 mL) at0° C. The reaction mixture was stirred at 25° C. for 2 hours. Water (10mL) was added and the mixture was adjusted to pH=9 with statured aqueousNa₂CO₃ solution, then extracted with DCM (20 mL×3). The combined organicphase was dried over Na₂SO₄ and concentrated in vacuo. The residue waspurified by flash silica gel chromatography (SiO₂, petroleumether:EtOAc=10:1 to 1:1, 0.1% Et₃N) to give the title compound as brownoil. LCMS (ESI) calculated for C₁₃H₁₉N₂O₂ (M+H)⁺: 235, found: 235.2.

Step 6—Preparation of (R)-methyl3-(7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydroquinolin-3-yl)propanoateand (S)-methyl3-(7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydroquinolin-3-yl)propanoate

To a mixture of (S and R)-methyl3-(7-amino-1,2,3,4-tetrahydroquinolin-3-yl)propanoate (290 mg, 1.238mmol) in DMSO (5.0 mL) was added3-methyl-1-(((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)-1H-imidazol-3-iumiodide (451 mg, 1.238 mmol). The reaction mixture was stirred at 25° C.for 30 minutes. The resulting mixture was diluted with water (10 mL) andextracted with ethyl acetate (3×10 mL). The organic layers wereseparated, combined, dried over Na₂SO₄, filtered and concentrated invacuo to give (S and R)-methyl3-(7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydroquinolin-3-yl)propanoateas a brown oil. LCMS (ESI) calculated for C₁₈H₂₄F₃N₂O₄ [M+H]⁺: 389,found: 389.2.

The product was resolved by SFC (Column: Chiralcel OD-3 150×4.6 mm I.D.,3 um Mobile phase: methanol (0.05% DEA) in CO₂ from 5% to 40% Flow rate:2.5 mL/min Wavelength: 220 nm to afford Isomer 1 (210 mg, brown oil;rT=5.2 min), Isomer 2 (206 mg, brown oil; rT=7.3 min).

Step 7. Preparation of (R)-3-(7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydroquinolin-3-yl)propanoic acid and(S)-3-(7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydroquinolin-3-yl)propanoicAcid

To a solution of (S or R)-methyl3-(7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydroquinolin-3-yl)propanoate(Isomer 1 from Step 6, 100 mg, 0.257 mmol) in 1,4-dioxane (2.0 mL) wasadded LiOH (37 mg, 1.545 mmol) and water (2.0 mL). The reaction mixturewas stirred at 25° C. for 2 h, then quenched with hydrochloric acid (1M, 5 mL). The resulting mixture was extracted with ethyl acetate (3×5mL). The organic layers were combined, dried over anhydrous magnesiumsulfate, filtered and concentrated in vacuo to afford the title compound(Isomer 1 from Step 7) as a yellow solid, which was used directly in thenext step without further purification.

The other enantiomer (Isomer 2 from Step 7) was prepared using a similarprocedure from Isomer 2 from Step 6 as described above. Both enantiomershave the same analytical data: LCMS (ESI) calculated for C₁₇H₂₂F₃N₂O₄[M+H]⁺: 375, found: 375.

Step 8—Preparation of(R)-3-(1-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydroquinolin-3-yl)propanoicacid and(S)-3-(1-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydroquinolin-3-yl)propanoicAcid

To a mixture of (R or S)-3-(7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydroquinolin-3-yl)propanoic acid(Isomer 1 from Step 7; 30 mg, 0.080 mmol) in tetrahydrofuran (0.5 mL)was added 3-chloro-1-ethyl-1H-pyrazole-4-sulfonyl chloride (46 mg, 0.201mmol) and pyridine (0.5 mL). The reaction mixture was stirred at 25° C.for 2 h, diluted with water (3 mL) and extracted with ethyl acetate (3mL×3). The organic layers were combined, dried over anhydrous magnesiumsulfate, filtered and concentrated in vacuo. The crude product waspurified by prep-HPLC (MeCN/water using TFA buffer) to afford the titlecompound (Isomer 1, Example 116A) as a white solid.

The other enantiomer (Isomer 2, Example 116B) was prepared from Isomer 2from Step 7 using a similar procedure as described above. Bothenantiomers have the same analytical data: LCMS (ESI) calculated forC₂₂H₂₇ClF₃N₄O₆S [M+H]⁺: 567, found: 567. ¹H NMR (400 MHz, CDCl₃) δ 8.06(1H, s), 7.85 (1H, s), 6.99 (1H, d, J=8.2 Hz), 6.87 (1H, d, J=7.4 Hz),6.67 (1H, br), 4.30 (1H, d, J=11.0 Hz), 3.10 (2H, q, J=7.0 Hz),3.28-3.40 (1H, m), 2.82 (1H, dd, J=16.2, 4.6 Hz), 2.50 (2H, t, J=7.4Hz), 2.32-2.44 (1H, m), 1.94-2.06 (2H, m), 1.78 (6H, s), 1.60-1.70 (1H,m), 1.47 (3H, t, J=7.2 Hz).

Example 117—Preparation of Additional1,2,3,4-Tetrahydroquinolin-3-yl)propanoic Acids

The compounds in Table 34 were prepared based on the experimentalprocedures described in Example 116, and can be achieved by one of skillin the art in light of the present disclosure.

TABLE 34 Ex. Observed No. Structure Name m/z 117A

(R or S)-3-(7-((((1,1,1- trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1- ((5-(trifluoromethyl)pyridin-3-yl)sulfonyl)-1,2,3,4- tetrahydroquinolin-3- yl)propanoic acid 584 [M +H]+ 117B

(R or S)-3-(1-((4-fluoro-3- methoxyphenyl)sulfonyl)-7-((((1,1,1-trifluoro-2- methylpropan-2- yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydroquinolin-3- yl)propanoic acid 563 [M + H]+ 117C

(R or S)-3-(7-((((1,1,1- trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-1- ((5-(trifluoromethyl)pyridin-3-yl)sulfonyl)-1,2,3,4- tetrahydroquinolin-3- yl)propanoic acid 584 [M +H]+ 117D

(R or S)-3-(1-((4-fluoro-3- methoxyphenyl)sulfonyl)-7-((((1,1,1-trifluoro-2- methylpropan-2- yl)oxy)carbonyl)amino)-1,2,3,4-tetrahydroquinolin-3- yl)propanoic acid 563 [M + H]+

Example 118—Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl(5-((3-chloro-1-ethyl-1-pyrazol-4-yl)sulfonyl)-8-oxo-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamateExample 118

Step 1—Preparation of tert-butyl7-nitro-3,4-dihydro-1,5-naphthyridine-1(2H)-carboxylate

A solution of tert-butyl 3-oxopiperidine-1-carboxylate (6 g, 30.1 mmol)and 1-methyl-3,5-dinitropyridin-2(1H)-one (7.20 g, 36.1 mmol) inmethanolic ammonia (1 M, 60 ml) was irradiated at 90° C. in a sealedvial for 45 min. The mixture was then concentrated and redissolved inCH₂Cl₂ (110 mL), the organics washed with saturated aqueous NaHCO₃ (100ml) and water (100 mL), dried over Na₂SO₄, and evaporated. The crudeproduct was purified by column chromatography (petroleum ether:ethylacetate=15:1-4:1) to give the title product as a light yellow solid.LCMS (ESI) calculated for C₁₃H₁₈N₃O₄ [M+H]⁺: 280.1, found: 280.2; ¹H-NMR(CDCl₃, 400 MHz) δ 8.97 (2H, s), 3.79-3.76 (2H, m), 3.06-3.02 (2H, m),2.06-2.00 (2H, m), 1.54 (9H, s).

Step 2—Preparation of5-(tert-butoxycarbonyl)-3-nitro-5,6,7,8-tetrahydro-1,5-naphthyridine1-oxide

A mixture of tert-butyl7-nitro-3,4-dihydro-1,5-naphthyridine-1(2H)-carboxylate (500 mg, 1.790mmol) and m-CPBA (618 mg, 3.58 mmol) in CH₂Cl₂ (15 mL) was stirred at20° C. for 18 hours. Additional CH₂Cl₂ (10 mL) was added to dissolve thesolids and the organics washed with saturated sodium bicarbonate, water,brine and dried over sodium sulfate. The solvent was removed to give thecrude title compound as a dark yellow solid, which was used directly inthe next step. LCMS (ESI) calculated for C₁₃H₁₈N₃O₅ [M+H]⁺: 296.1,found: 296.1.

Step 3—Preparation of tert-butyl4-acetoxy-7-nitro-3,4-dihydro-1,5-naphthyridine-1(2H)-carboxylate

A mixture of5-(tert-butoxycarbonyl)-3-nitro-5,6,7,8-tetrahydro-1,5-naphthyridine1-oxide (503 mg, 1.703 mmol), Ac₂O (6 ml, 63.6 mmol) and toluene (6 mL)was heated to reflux for 5 hours under nitrogen. The reaction wasconcentrated under vacuum and azeotroped three times with toluene togive the crude title compound as black oil. LCMS (ESI) calculated forC₁₅H₂₀N₃O₆ [M+H]⁺: 338.1, found: 338.1; ¹H-NMR (CDCl₃, 400 MHz) δ 9.19(1H, s), 9.07 (1H, d, J=2.0 Hz), 6.04-6.01 (1H, m), 4.17-4.12 (2H, m),3.69-3.63 (2H, m), 2.15 (3H, s), 1.58 (9H, s).

Step 4—Preparation of tert-butyl4-hydroxy-7-nitro-3,4-dihydro-1,5-naphthyridine-1(2H)-carboxylate

A mixture of tert-butyl4-acetoxy-7-nitro-3,4-dihydro-1,5-naphthyridine-1(2H)-carboxylate (592mg, 1.755 mmol) and 2N potassium carbonate (2.63 ml, 5.26 mmol) in MeOH(8 ml) and THF (8 mL) was stirred at 20° C. for 15 h. The organicsolvents were removed under vacuum and the aqueous residue extractedwith ethyl acetate (3×12 mL). The organic layer was washed with brine (8mL) and dried over sodium sulfate. The solvent was removed and the crudeproduct was purified by column chromatography (petroleum ether:ethylacetate=3:1) to give the titled compound as a yellow oil. ¹H-NMR (CDCl₃,400 MHz) δ 9.11 (1H, s), 8.96 (1H, d, J=1.6 Hz), 4.71-4.67 (1H, m), 4.11(1H, s), 3.90-3.85 (1H, m), 3.74-3.68 (1H, m), 2.41-2.36 (1H, m),1.86-1.80 (1H, m), 1.51 (9H, s).

Step 5—Preparation of tert-butyl7-nitro-4-oxo-3,4-dihydro-1,5-naphthyridine-1(2H)-carboxylate

A mixture of tert-butyl4-hydroxy-7-nitro-3,4-dihydro-1,5-naphthyridine-1(2H)-carboxylate (291mg, 0.985 mmol) and manganese (IV) oxide (857 mg, 9.85 mmol) in CH₂Cl₂(10 mL) was stirred at 25° C. for 18 hours. Additional CH₂Cl₂ (15 mL)was added, the solution filtered and the filtrate concentrated undervacuum. The residue was purified by column chromatography (petroleumether:ethyl acetate=3:1) to give the title compound as a yellow solid.¹H-NMR (CDCl₃, 400 MHz) δ 9.23 (2H, s), 4.29 (2H, t, J=6.4 Hz),3.02-2.98 (2H, m), 1.61 (9H, s).

Step 6—Preparation of tert-butyl4,4-difluoro-7-nitro-3,4-dihydro-1,5-naphthyridine-1(2H)-carboxylate

To a solution of tert-butyl7-nitro-4-oxo-3,4-dihydro-1,5-naphthyridine-1(2H)-carboxylate (184 mg,0.627 mmol) in CH₂Cl₂ (8 mL) was added DAST (2 mL, 15.14 mmol) at −20°C. under nitrogen. The reaction was allowed to warm up to 20° C. slowlyand stirred at 20° C. for 18 h. The resulting mixture was diluted withCH₂Cl₂ (15 mL), poured into cooled sat. NaHCO₃ (10 mL) and extractedwith CH₂Cl₂ (3×15 mL). The combined organic layers were washed withbrine (8 mL), dried over anhydrous Na₂SO₄, filtered and concentrated.The crude product was purified by column chromatography (petroleumether:ethyl acetate=9:1) to afford the title compound as yellow solid.¹H-NMR (CDCl₃, 400 MHz) δ 9.27 (1H, s), 9.17 (1H, d, J=2.0 Hz),4.10-4.05 (2H, m), 2.60-2.51 (2H, m), 1.58 (9H, s).

Step 7—Preparation of tert-butyl7-amino-4,4-difluoro-3,4-dihydro-1,5-naphthyridine-1(2H)-carboxylate

To a solution of tert-butyl4,4-difluoro-7-nitro-3,4-dihydro-1,5-naphthyridine-1(2H)-carboxylate(120 mg, 0.381 mmol) in EtOAc (8 mL) was added nickel (11.17 mg, 0.190mmol) in one portion at 25° C. under nitrogen. The reaction was stirredat 25° C. under H₂ (15 psi) for 4 hours, then filtered and evaporated toafford crude tert-butyl7-amino-4,4-difluoro-3,4-dihydro-1,5-naphthyridine-1(2H)-carboxylate asa yellow oil. LCMS (ESI) calculated for C₁₃H₁₈F₂N₃O₂ [M+H]⁺: 286.1,found: 286.3.

Step 8—Preparation of tert-butyl4,4-difluoro-7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-1,5-naphthyridine-1(2H)-carboxylate

To a solution of tert-butyl7-amino-4,4-difluoro-3,4-dihydro-1,5-naphthyridine-1(2H)-carboxylate (65mg, 0.228 mmol) and3-methyl-1-(((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)-1H-imidazol-3-iumiodide (83 mg, 0.228 mmol) in DMSO (2 mL) was stirred at 20° C. undernitrogen for 24 hours. The reaction was diluted with EtOAc (10 mL) andwashed with brine (3×6 mL). The organic layer was dried over Na₂SO₄,filtered, and the filtrate was concentrated in vacuum to give crudetitle compound as yellow solid. LCMS (ESI) calculated for C₁₈H₂₃F₅N₃O₄[M+H]⁺: 440.2, found: 440.1.

Step 9—Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl(8-oxo-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate

To a solution of tert-butyl4,4-difluoro-7-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-1,5-naphthyridine-1(2H)-carboxylate(43 mg, 0.098 mmol) in EtOAc (1 mL) was added a solution of HCl in EtOAc(3 ml, 4 N). The reaction was stirred at 20° C. for 2 h, thenconcentrated to give the crude title compound as yellow oil. LCMS (ESI)calculated for C₁₃H₁₅F₃N₃O₃ [M+H]⁺: 318.1, found: 318.0.

Step 10—Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl(5-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-8-oxo-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate

To a mixture of 1,1,1-trifluoro-2-methylpropan-2-yl(8-oxo-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate (10 mg, 0.032mmol) in THF (1 mL) was added 3-chloro-1-ethyl-1H-pyrazole-4-sulfonylchloride (14.4 mg, 0.063 mmol) and pyridine (1 mL). The reaction wasstirred at 25° C. for 16 hours, then diluted with water (3 mL) andextracted with ethyl acetate (3×6 mL). The organic layers were combined,dried over anhydrous magnesium sulfate, filtered and concentrated invacuum. The crude product was purified by prep-HPLC (MeCN/water usingTFA buffer) to afford the title compound as white solid. LCMS (ESI)calculated for C₁₈H₂₀ClF₃N₅O₅S [M+H]⁺: 510.1, found: 510.0; ¹H-NMR(CDCl₃, 400 MHz) δ 8.57 (1H, s), 8.14 (1H, s), 7.46 (1H, s), 4.34 (s,2H), 4.08 (2H, d, J=7.2 Hz), 2.90 (2H, s), 1.71 (6H, s), 1.46 (3H, s).

Example 119—Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl(1-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-4-oxo-1,2,3,4-tetrahydroquinolin-7-yl)carbamate(Example 119)

Step 1—Preparation of 1,2,3,4-tetrahydroquinolin-7-amine

7-nitro-1,2,3,4-tetrahydroquinoline (2 g, 11.22 mmol) and Pd/C (1.2 g)in EtOH (20 mL) were stirred under H₂ at 25° C. for 1 h, then filtered.The filtrate was concentrated to obtain the crude product as black oil,which was used in the next step without further purification. LCMS (ESI)calculated for C₉H₁₃N₂ [M+H]⁺: 149, found: 149 ¹H NMR (CDCl₃ 400 MHz,) δ6.68-6.75 (1H, m), 5.99 (1H, dd, J=2.0, 7.8 Hz), 5.78-5.86 (1H, m),3.21-3.25 (2H, m), 2.63 (2H, t, J=6.3 Hz, 2H), 1.85-1.92 (2H, m).

Step 2—Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl(1,2,3,4-tetrahydroquinolin-6-yl)carbamate

To a solution of 1,2,3,4-tetrahydroquinolin-6-amine (1.2 g, 8.10 mmol)and3-methyl-1-(((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)-1H-imidazol-3-iumiodide (1.921 g, 8.10 mmol) in 15 mL of DMSO was stirred at 25° C. for 2h. The reaction was quenched with H₂O and extracted with EtOAc. Theorganic layer was dried, concentrated and the crude product was purifiedby column chromatography (petroleum ether:EtOAc=10:1) to give1,1,1-trifluoro-2-methylpropan-2-yl(1,2,3,4-tetrahydroquinolin-6-yl)carbamate as yellow solid. LCMS (ESI)calculated for C₁₄H₁₇F₃N₂O₂ [M+H]⁺: 303, found: 303 ¹H NMR (CDCl₃ 400MHz) δ 6.82 (1H, d, J=8.2 Hz), 6.64 (1H, br s), 6.50 (1H, br s), 6.40(1H, d, J=7.4 Hz), 3.22-3.28 (2H, m), 2.67 (2H, t, J=6.1 Hz, 2H), 1.89(2H, d, J=5.8 Hz, 2H), 1.72 (6H, s).

Step 3-Preparation of1,1,1-trifluoro-2-methylpropan-2-yl(1-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamate

To a solution of 1,1,1-trifluoro-2-methylpropan-2-yl(1,2,3,4-tetrahydroquinolin-7-yl)carbamate (200 mg, 0.662 mmol) andpyridine (105 mg, 1.32 mmol) in THF (2 mL) was added4-fluoro-3-(trifluoromethyl)benzene-1-sulfonyl chloride (347 mg, 1.323mmol) and the reaction mixture was stirred at 80° C. overnight, thenextracted with EtOAc and water. The combined organic phase was washedwith brine, dried over sodium sulfate, and concentrated in vacuo. Thecrude product was purified by prep-TLC (petroleum ether:EtOAc=10:1) togive crude title product as colorless oil, which was taken forwardwithout further purification. ¹H NMR (CDCl₃, 400 MHz) δ 7.94 (1H, d,J=5.1 Hz), 7.80-7.66 (2H, m), 7.16 (1H, s), 7.12-7.04 (1H, m), 6.91 (1H,d, J=8.2 Hz), 6.60 (1H, brs), 3.81-3.72 (2H, m), 2.42 (2H, t, J=6.5 Hz),1.70 (6H, s), 1.67-1.61 (2H, m).

Step 4-Preparation of1,1,1-trifluoro-2-methylpropan-2-yl(1-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-4-oxo-1,2,3,4-tetrahydroquinolin-7-yl)carbamate

To a solution of1,1,1-trifluoro-2-methylpropan-2-yl(1-((4-fluoro-3-(trifluromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydroquinolin-7-yl)carbamate(200 mg, 0.378 mmol) in n-butanol (5 mL) was added solution of KMnO₄(269 mg, 1.703 mmol) and KH₂PO₄ (232 mg, 1.703 mmol) solution (dissolvedin 1 mL H₂O) in portions at 0° C. The reaction was stirred at 15° C.overnight, then quenched with H₂O and extracted with EtOAc. The organiclayer was dried and concentrated to give1,1,1-trifluoro-2-methylpropan-2-yl(1-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-4-oxo-1,2,3,4-tetrahydroquinolin-7-yl)carbamateas colorless oil. LCMS (ESI) calculated for C₂₁H₁₈F₇N₂O₅S [M+H]⁺: 543.1,found: 543.0.

Example 120—Preparation of (R or S)-1,1,1-trifluoro-2-methylpropan-2-yl(6-methyl-8-oxo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate(Example 120)

Step 1—Preparation of 2,5-dibromopyridin-3-amine

To a solution of 2,5-dibromo-3-nitropyridine (13.00 g, 46.1 mmol) inacetone (150 mL) was added ammonium chloride (24.67 g, 461 mmol) andzinc dust (15.08 g, 231 mmol) and the resulting mixture was stirred atroom temperature for 5 h under N₂. Water (100 mL) was next added and theaqueous layer was extracted with EtOAc (3×200 mL). The combined organiclayers were concentrated in vacuo and the crude product was purified byflash chromatography (0-30% EtOAc in petroleum ether) to afford thetitle compound as a white solid. ¹H NMR (400 MHz, MeOD) δ 7.67 (d, J=2.0Hz, 1H), 7.29 (d, J=2.0 Hz, 1H).

Step 2. Preparation ofN-(2,5-dibromopyridin-3-yl)-3-(trifluoromethyl)-N-((3-(trifluoromethyl)phenyl)sulfonyl)benzenesulfonamide

To a solution of 2,5-dibromopyridin-3-amine (1.00 g, 3.97 mmol) in THF(15 mL) and pyridine (15 mL) was added3-(trifluoromethyl)benzene-1-sulfonyl chloride (1.16 g, 4.74 mmol) andthe resulting mixture was stirred at room temperature for 18 h under N₂.The reaction was quenched with aqueous NH₄Cl (20 mL) and the aqueouslayer was extracted with EtOAc (3×50 mL). The combined organic layerswere concentrated in vacuo to afford the title compound as yellow solid.LCMS (ESI) calculated for C₁₉H₁₁Br₂F₆N₂O₄S₂ [M+H]⁺: 666.8, found: 668.7.

Step 3—Preparation ofN-(2,5-dibromopyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide

To a solution ofN-(2,5-dibromopyridin-3-yl)-3-(trifluoromethyl)-N-((3-(trifluoromethyl)phenyl)sulfonyl)benzenesulfonamide(10.0 g, 14.97 mmol) in MeOH (30 mL) was added KOH (4.20 g, 74.8 mmol)in water (10 mL). The resulting mixture was stirred at 60° C. for 2 hunder N₂. The solution was adjusted to pH=4 with 1 M HCl and the aqueouslayer was extracted with EtOAc (3×100 mL). The combined organic layerswere concentrated in vacuo and the crude product was purified by flashchromatography (0-50% EtOAc in petroleum ether) to afford the titlecompound as yellow oil. ¹H NMR (400 MHz, MeOD) 8.29 (d, J=1.6 Hz, 1H),8.00-8.11 (m, 2H), 7.95 (d, J=7.4 Hz, 2H), 7.66-7.78 (m, 1H).

Step 4-Preparation ofN-(2,5-dibromopyridin-3-yl)-N-(pent-4-en-2-yl)-3-(trifluoromethyl)benzenesulfonamide

To a solution ofN-(2,5-dibromopyridin-3-yl)-3-(trifluoromethyl)benzenesulfonamide (5.00g, 10.87 mmol) in THF (50 mL) was added triphenylphosphine (3.42 g,13.04 mmol), pent-4-en-2-ol (1.12 g, 13.00 mmol) and (E)-diethyldiazene-1,2-dicarboxylate (2.27 g, 13.03 mmol) at room temperature. Theresulting mixture was heated to 60° C. for 36 h, then treated with 100mL of water. The aqueous layer was extracted with EtOAc (3×100 mL) andthe combined organic layers were concentrated in vacuo. The crudeproduct was purified by flash chromatography (0-20% EtOAc in petroleumether) to afford the title compound as a white solid. LCMS (ESI)calculated for C₁₇H₁₆Br₂F₃N₂O₂S [M+H]⁺: 526.9, found: 529.0.

Step 5—Preparation of7-bromo-2-methyl-4-methylene-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydro-1,5-naphthyridine

To a solution ofN-(2,5-dibromopyridin-3-yl)-N-(pent-4-en-2-yl)-3-(trifluoromethyl)benzenesulfonamide(500 mg, 0.95 mmol) in 1,4-dioxane (20 mL) was added Cs₂CO₃ (617 mg,1.89 mmol), followed by Pd₂(dba)₃ (43 mg, 0.047 mmol). The resultingmixture was stirred at 80° C. for 18 h under N₂, then concentrated invacuo. The crude product was purified by flash chromatography (0-20%EtOAc in petroleum ether) to afford the title compound as a white solid.LCMS (ESI) calculated for C₁₇H₁₅BrF₃N₂O₂S [M+H]⁺: 447.0, found: 449.0,¹H NMR (400 MHz, MeOD) 8.51 (br s, 1H), 7.94-8.09 (m, 3H), 7.72-7.85 (m,2H), 5.52-5.75 (m, 1H), 4.93-5.09 (m, 2H), 4.15-4.34 (m, 1H), 2.71-2.82(m, 1H), 2.24-2.34 (m, 1H), 2.03-2.16 (m, 1H), 1.22 (d, J=6.6 Hz, 2H),1.15 (d, J=6.6 Hz, 1H).

Step 6—Preparation of7-bromo-2-methyl-1-((3-(trifluoromethyl)phenyl)sulfonyl)-2,3-dihydro-1,5-naphthyridin-4(1H)-one

To a solution of7-bromo-2-methyl-4-methylene-1-((3-(trifluoromethyl)phenyl)sulfonyl)-1,2,3,4-tetrahydro-1,5-naphthyridine(400 mg, 0.89 mmol) in MeOH (20 mL) was added sodium periodate (574 mg,2.68 mmol), followed by aqueous osmium tetroxide (0.056 mL, 0.18 mmol)and water (10 mL). The resulting mixture was stirred at room temperaturefor 3 h under N₂, then concentrated in vacuo. The crude product waspurified by flash chromatography (0-20% EtOAc in petroleum ether) toafford the title compound as a white solid. LCMS (ESI) calculated forC₁₆H₁₃BrF₃N₂O₃S [M+H]⁺: 449.0, found: 449.1.

Step 7—Preparation of (R)-tert-butyl(6-methyl-8-oxo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamateand (S)-tert-butyl(6-methyl-8-oxo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate

To a solution of7-bromo-2-methyl-1-((3-(trifluoromethyl)phenyl)sulfonyl)-2,3-dihydro-1,5-naphthyridin-4(1H)-one(120 mg, 0.27 mmol) in 1,4-Dioxane (2 mL) was added Cs₂CO₃ (174 mg, 0.53mmol), followed by tert-butyl carbamate (62 mg, 0.53 mmol) and (RuPhos)palladium(II) phenethylamine chloride (10 mg, 0.014 mmol). The resultingmixture was stirred at 90° C. for 18 h under N₂, then filtered andwashed with EtOAc (20 mL). The combined organics were removed in vacuoand the crude product was purified by prep-HPLC (MeCN/water using TFAbuffer) to afford the title racemate as a white solid.

The above racemic mixture was separated by chiral SFC (Column: IC250×4.6 mm I.D., 5 um; Mobile phase: iso-propanol (0.05% DEA) in CO₂from 5% to 40%; Flow rate: 2.5 mL/min; Wavelength: 220 nm) to afford twoenantiomers (faster eluent, Isomer 1 from Step 7 and slower eluent,Isomer 2 from Step 7), which have the same analytical data: LCMS (ESI)calculated for C₂₁H₂₃F₃N₃O₅S [M+H]⁺: 486.1, found: 486.3, ¹H NMR (400MHz, MeOD) 8.53 (d, J=11.7 Hz, 2H), 7.92-8.03 (m, 3H), 7.78 (t, J=7.8Hz, 1H), 4.64 (br s, 1H), 2.96 (br s, 1H), 1.82-1.89 (m, 1H), 1.55 (s,9H), 0.97 (d, J=6.6 Hz, 3H).

Step 8—Preparation of(R)-7-amino-2-methyl-1-((3-(trifluoromethyl)phenyl)sulfonyl)-2,3-dihydro-1,5-naphthyridin-4(1H)-oneand(S)-7-amino-2-methyl-1-((3-(trifluoromethyl)phenyl)sulfonyl)-2,3-dihydro-1,5-naphthyridin-4(1H)-one

To a solution of (R or S)-tert-butyl(6-methyl-8-oxo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate(Isomer 1 from Step 7, 10 mg, 0.021 mmol) in DCM (1 mL) was added TFA (2mL, 26.0 mmol). The reaction mixture was stirred at room temperature for3 h, then concentrated in vacuo to afford the title compound ascolorless oil.

The other enantiomer (Isomer 2 from Step 8) was prepared using a similarprocedure as described above from Isomer 2 from Step 7. Both enantiomershave same analysis data: LCMS (ESI) calculated for C₁₆H₁₅F₃N₃O₃S [M+H]⁺:386.1, found: 386.1.

Step 9. Preparation of (R or S)-1,1,1-trifluoro-2-methylpropan-2-yl(6-methyl-8-oxo-5-((3-(trifluoromethyl)phenyl)sulfonyl)-5,6,7,8-tetrahydro-1,5-naphthyridin-3-yl)carbamate

To a solution of (R orS)-7-amino-2-methyl-1-((3-(trifluoromethyl)phenyl)sulfonyl)-2,3-dihydro-1,5-naphthyridin-4(1H)-one(Isomer 1 from Step 8, 7 mg, 0.018 mmol) in DMSO (1 mL) was added3-methyl-1-(((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)-1H-imidazol-3-iumiodide (10 mg, 0.027 mmol). The reaction mixture was stirred at roomtemperature for 16 h and then purified by prep-HPLC (MeCN/water usingTFA buffer) to afford the title compound as a white solid.

LCMS (ESI) calculated for C₂₁H₂₀F₆N₃O₅S [M+H]⁺: 540.1, found: 540.1, ¹HNMR (400 MHz, MeOD) 8.46 (d, J=14.1 Hz, 2H), 7.94 (d, J=16.8 Hz, 3H),7.76 (t, J=7.8 Hz, 1H), 4.63 (brs, 1H), 2.90 (d, J=10.2 Hz, 1H), 1.85(brs, 1H), 1.77 (s, 3H), 1.18 (d, J=6.7 Hz, 3H), 0.94 (d, J=6.7 Hz, 3H).

Example 121: Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl ((R andS)-2-((R andS)-5-oxopyrrolidin-2-yl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(Example 121)

Step 1—Preparation of (R and S)-tert-butyl 2-((R andS)-6-nitro-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-5-oxopyrrolidine-1-carboxylate

A mixture of benzyltriethylammonium chloride (40 mg, 0.176 mmol), K₂CO₃(122 mg, 0.88 mmol), 2-(benzylamino)-4-nitrophenol (322 mg, 1.32 mmol)and tert-butyl 2-(oxiran-2-yl)-5-oxopyrrolidine-1-carboxylate (200 mg,0.880 mmol) in DMF (5 mL) was stirred at 100° C. for 16 h. The reactionmixture was diluted with ethyl acetate, washed with brine, dried andconcentrated, then purified by prep-TLC (petroleum ether/ethylacetate=1:1) to afford the title compound as a white solid. LCMS (ESI)calculated for C₂₄H₂₈N₃O₈S [M+H]⁺: 518 found 518.

Step 2—Preparation of (R and S)-5-((R andS)-6-nitro-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)pyrrolidin-2-one

To a solution of (R and S)-tert-butyl 2-((R andS)-6-nitro-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-5-oxopyrrolidine-1-carboxylate(400 mg, 0.773 mmol) in DCM (5 mL) was added TFA (441 mg, 3.86 mmol).The reaction mixture was stirred at 30° C. for 6 h, then washed with aq.NaHCO₃ and brine, dried over sodium sulfate, filtered and concentratedto afford the title compounds as yellow oil. LCMS (ESI) calculated forC₁₉H₂₀N₃O₆S [M+H]⁺: 418, found 418, ¹H NMR (400 MHz, CDCl₃) δ 8.19-8.27(1H, m), 8.08-8.17 (1H, m), 7.82-7.95 (1H, m), 7.67 (2H, brs), 7.32-7.43(2H, m), 4.20-4.33 (1H, m), 3.67-3.92 (2H, m), 3.44-3.64 (1H, m), 2.46(3H, s), 2.21-2.43 (4H, m).

Step 3—Preparation of (R and S)-5-((R andS)-6-amino-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)pyrrolidin-2-one

10% Pd/C (122 mg, 0.115 mmol) was added to a solution of (R and S)-5-((RandS)-6-nitro-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)pyrrolidin-2-one(160 mg, 0.383 mmol) in methanol (10 mL). The reaction mixture wasstirred at room temperature for 16 h under a H₂ balloon, then filteredthrough CELITE and concentrated to afford the titled compound ascolorless oil. LCMS (ESI) calculated for C₁₉H₂₂N₃O₄S [M+H]⁺: 388, found388.

Step 4—Preparation of 1,1,1-trifluoro-2-methylpropan-2-yl ((R andS)-2-((R andS)-5-oxopyrrolidin-2-yl)-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate

To a solution of (R and S)-5-((R andS)-6-amino-4-tosyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)pyrrolidin-2-one(9 mg, 0.023 mmol) in DMSO (3 mL) was added1-iodo-1-methyl-3-(((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)-2,3-dihydro-1H-imidazol-1-ium-2-ide(9 mg, 0.025 mmol) and the resulting mixture was stirred at 20° C. for 1h. Then water was added and the mixture extracted with ethyl acetate (10mL×2). The combined organic layers were washed with water and brine,concentrated and the crude product was purified by preparative HPLC(MeCN/water using TFA buffer) to afford the title compound as whitesolid. LCMS (ESI) calculated for C₂₄H₂₇F₃N₃O₆S [M+H]⁺: 542 found 542. ¹HNMR (400 MHz, CDCl₃) δ 7.70 (1H, br s), 7.60 (2H, d, J=8.2 Hz), 7.30(2H, d, J=7.8 Hz), 7.19-7.25 (1H, m), 6.78-6.85 (1H, m), 6.47-6.69 (2H,m), 4.05-4.26 (1H, m), 3.77-3.87 (1H, m), 3.63-3.87 (1H, m), 3.31 (2H,d, J=8.2 Hz), 2.43 (3H, s), 2.34-2.41 (3H, m), 1.97-2.11 (1H, m), 1.78(6H, s).

Biological Assays

The compounds of the invention inhibit RORgammaT activity. Activation ofRORgammaT activity can be measured using, e.g., a biochemical TR-FRETassay. In such an assay, interaction of cofactor-derived peptides withhuman RORgammaT-Ligand Binding Domain (LBD) can be measured. The TR-FRETtechnique is a sensitive biochemical proximity assay that will giveinformation concerning the interaction of a ligand with the LBD, in thepresence of cofactor-derived peptides (Zhou et al., Methods 25:54-61,2001).

To identify novel antagonists of RORgammaT, an assay was developed whichemploys the interaction of RORgammaT with its co-activator peptideSRC1_2. This peptide mimics the recruitment of co-activators toRORgammaT through its interaction with the LXXLL (SEQ ID NO:1) (e.g., NRbox) motifs (Xie et al., J. Immunol. 175: 3800-09, 2005; Kurebayashi etal., Biochem. Biophys. Res. Commun. 315: 919-27, 2004; Jin et al., Mol.Endocrinology 24:923-29, 2010). The RORγ-Ligand Binding Domain TR-FRETAssay was run according to the following protocol.

HIS-tagged RORγ-LBD protein was recombinantly expressed in Escherichiacoli. The RORγ-LBD protein was purified by Ni²⁺-affinity resin. Purifiedprotein was then diluted in assay buffer (50 mM Tris pH 7.0, 50 mM KCl,1 mM EDTA, 0.1 mM DTT, 100 μg/mL bovine serum albumin, delipidated) toobtain a RORγ-LBD final concentration of 3 nM. Europium tagged anti-HISantibody was also added to this solution (1.25 nM). Separately, SF9cells not expressing any recombinant protein were lysed (32,000 cellsper μl in 25 mM Tris, 50 mM NaCl) and the previously frozen lysate wasadded to the diluted RORγ-LBD solution at a ratio of 0.75 μl SF9 lysateper 15 μl of diluted RORγ-LBD.

Compounds to be tested were injected to the 384-well assay plate usingAcoustic Droplet Ejection technology by Echo 550 liquid handler(Labcyte, CA).

A stock of biotinylated-LXXLL peptide from coactivator SRC1(Biotin-SPSSHSSLTERHKILHRLLQEGSP) (SEQ ID NO:2) and APC-conjugatedstreptavidin (final concentrations 100 nM and 8 nM respectively) werealso added to each well.

The final assay mixture was incubated overnight at 4° C., warmed to roomtemperature and the fluorescence signal was measured on an Envisionplate reader: (Excitation filter=340 nm; APC emission=665 nm; Europiumemission=615 nm; dichroic mirror=D400/D630; delay time=100 μs,integration time=200 μs). IC₅₀ values for test compounds were calculatedfrom the quotient of the fluorescence signal at 665 nm divided by thefluorescence signal at 615 nm.

The IC₅₀ values for representative compounds of the invention are setforth below.

Ex. No. IC₅₀ (nM) 1 3.011 2A 8.586 2B 8.547 2C 4.571 2D 7.99 2E 237.6 2F9.743 2G 15.18 2H 11.27 3 325.2 4A 28.44 4B 6.772 5 25.79 6 11.84 783.41 8 31.65 9 4.229 10A 41.73 10B 158.9 10C 22.78 10D 10.45 10E 18.3610F 47.27 10G 29.41 10H 18.97 10i 72.52 10J 10.77 10K 195 11 5.79 122.723 13A 7.25 13B 12.72 13C 7.315 13D 11.64 13E 6.611 13F 14.53 13G56.79 13H 36.86 13i 15.7 13J 5.74 13K 27.75 13L 9.327 13M 5.42 13N 20.0213o 27.51 13P 15.72 13Q 15.41 13R 24.43 13S 14.6 13T 9.188 13U 8.801 13V5.297 13W 5.999 13X 10.1 13Y 3.045 13Z 5.817 13AA 5.903 13AB 3.916 13AC8.073 13AD 5.112 13AE 4.81 13AF 3.928 14 4.129 15A 7.388 15B 9.537 15C7.751 15D 10.27 15E 5.877 15F 5.184 16 4.16 17A 5.552 17B 11.25 17C4.808 17D 5.135 17E 7.841 17F 3.861 18 3.276 19A 6.322 19B 13.1 19C6.113 19D 5.331 19E 5.08 20 10.08 21 692.6 22A 920.1 22B 10.04 23A 467423B 27.72 24 11.56 25A 12.33 25B 11.49 25C 623.3 25D 203.1 25E 167.9 25F9593 25G 51.31 25H 107.6 26 30.68 27 29.17 28A 189.8 28B 20.67 28C 450.528D 847.7 28E 189.9 28F 1765 29 3.758 30A 2.241 30B 3.126 30C 2.154 30D15.83 30E 4.943 31 54.68 32A 16.34 32B 9.557 32C 51.75 32D 19.93 32E563.2 32F 241.6 32G 81.56 32H 26.59 33 43.31 34A 155.5 34B 60.79 34C54.12 34D 182.2 34E 58.3 35 17.25 36 10.01 37A 3.889 37B 3.656 37C 7.09137D 4.805 37E 6.015 37F 11.03 37G 19.84 37H 2.805 37i 4.835 37J 1.96137K 6.884 37L 7.555 37M 7.898 37N 7.056 37o 5.743 37P 7.645 37Q 10.7737R 3.79 37S 4.47 37T 19.13 37U 5.462 37V 6.858 37W 9.682 37X 8.031 37Y10.78 37Z 6.021 37AA 2.526 37AB 45.75 37AC 11.97 37AD 4.711 37AE 4.37937AF 4.164 37AG 2.557 37AH 2.113 37Ai 13.4 37AJ 5.726 37AK 12.82 37AL8.413 37AM 6.153 37AN 9.446 37Ao 5.409 37AP 9.273 37AQ 10.16 37AR 17.5138A 4.691 38B 6.584 38C 6.948 38D 4.871 38E 50.09 38F 42.52 38G 12.5 39140.4 40 1136 41 36.68 42 19.25 43A 128.5 43B 58.86 43C 41.18 43D 35.5343E 73.44 43F 50.44 43G 46.62 43H 24.9 43i 26.98 43J 97.22 43K 41.3 43L91.23 43M 55.32 43N 63.3 43o 110.2 43P 62.94 43Q 36.63 43R 36.23 43S31.14 43T 60.69 43U 47.48 43V 33.19 43W 534.5 43X 212.8 43Y 72.99 43Z57.26 43AA 99.03 43AB 85.9 43AC 72.84 43AD 296.8 44 4.073 45A 126.9 45B12.63 45C 43.79 45D 63.16 45E 25.19 45F 11.25 45G 5.587 45H 14.64 45i17.1 45J 6.848 45K 6.301 46 12.09 47A 12.26 47B 8.827 47C 5.714 47D5.982 47E 5.951 47F 27.74 47G 26.58 47H 5.975 48 5.72 49 2.464 50 4.82851 42.66 52 6.14 53A 4.073 53B 6.26 53C 4.878 53D 5.515 53E 4.379 53F6.138 53G 7.733 53H 6.766 53i 4.975 53J 6.373 53K 10.55 53L 5.987 53M15.2 53N 68.44 53o 53.11 53P 3.423 53Q 10.17 54 3.489 55A 3.133 55B7.848 55C 8.624 55D 136.2 55E 4.09 56 4.919 57A 5.667 57B 3.987 57C6.441 57D 4.524 57E 4.173 57F 7.503 57G 5.759 57H 10.64 57i 8.268 57J12.49 57K 10.96 57L 12.5 57M 393.6 57N 30.88 57o 12.83 57P 11.69 57Q7.383 57R 13.8 57S 14.85 57T 12.7 58 3.564 59 4.77 60 5.973 61 14.9 628.874 63A 21.18 63B 9.753 63C 3.037 63D 37.89 63E 2.798 63F 2.782 63G5.595 63H 8.436 64 16.59 65 4.573 66 6.846 67A 4.899 67B 5.793 67C 23.1967D 21.57 67E 38.19 72 314.5 73 903.5 74A 194.8 74B 902.5 74C 4955 751923 76A 3309 76B 270.2 77 192.2 78A 830 78B 312.6 79A 63.48 79B 130.179C 603 79D 189.8 80 330.4 6B 40.02 13AG 5.84 57U 19.43 81A 99.79 81B28.43 81C 5.137 81D 16.03 81E 9.026 81F 3.325 81G 27.02 82A 231.4 82B8.849 82C 157.8 82D 7.904 83 4.808 84 7.487 85 13.84 86 64.76 87 232.888A 7.651 88B 5.954 89A 22.56 89B 12.94 90A 26.14 90B 6.971 91A 26.1491B 6.971 91C 6.966 91D 15.85 91E 13.89 91F 18.09 91G 147.7 91H 9.3 91i24.42 91J 70.36 91K 42.73 92 3.109 93A 5.389 93B 32.15 94A 74.69 94B4.792 95A 32.31 95B 137.6 95C 78.9 95D 5.727 95E 4.518 95F 524.4 95G10.12 96 26.17 97A 12.55 97B 29.01 98A 40.06 98B 46.07 98C 1436 98D29.74 98E 44.81 98F 10.82 98G 38.66 98H 6.325 98i 41.49 98J 28.06 998.291 100 10.36 101 11.67 102 11.2 103A 119.7 103B 28.22 104A 11.2 104B12.65 104C 8.77 104D 11.87 104E 9.238 104F 50.7 104G 119.7 104H 15.24104i 28.22 105 6.303 106 5.708 107A 6.081 107B 7.533 108 6.621 109A12.62 109B 39.56 109C 8.263 110 62.3 111A 2724 111B 78.26 112A 72.09112B 288.9 113 12.35 114A 3.869 114B 4.194 114C 6.863 114D 3.456 115A2.026 115B 4.961 116A 9.578 116B 8.798 117A 10.47 117B 6.515 117C 7.75117D 5.748 118 720.5 119 4.49

While the present invention has been described in conjunction with thespecific embodiments set forth above, many alternatives, modifications,and other variations thereof will be apparent to those of ordinary skillin the art in light of the present disclosure. All such alternatives,modifications, and variations are intended to fall within the spirit andscope of the present invention.

What is claimed is:
 1. A compound of the Formula (I)

or a pharmaceutically acceptable salt thereof, wherein: X¹ is C(R²); X²is O; R¹ is H, C₁-C₃ alkyl, or C₁-C₃ alkyl substituted by hydroxy; R² isH, halo, or C₁-C₃ alkyl; R³ is selected from the group consisting of:(a.) H; (b.) C₁-C₆ alkyl; (c.) —(C(R^(a))₂)_(n1)OH; (d.)—(C(R^(a))₂)_(n1)N(R^(b))₂; (e.) —(C(R^(a))₂)_(n1)N(H)C(O)N(R^(b))₂;(f.) —(C(R^(a))₂)_(n1)N(H)C(O)R^(d); (g.)—(C(R^(a))₂)_(n1)N(H)S(O)₂N(R^(b))₂; (h.)—(C(R^(a))₂)_(n1)N(H)S(O)₂R^(d); (i.) —(C(R^(a))₂)_(n2)CO₂R^(c); (j.)—(C(R^(a))₂)_(n2)C(O)N(R^(b))₂; (k.) —(C(R^(a))₂)_(n1)S(O)₂N(R^(b))₂;(l.) —(C(R^(a))₂)_(n2)N(H)C(O)OR^(d); (m.)—(C(R^(a))₂)_(n2)C(O)N(H)S(O)₂R^(d); (n.)—(C(R^(a))₂)_(n1)N(H)S(O)₂OR^(d); (o.) —(C(R^(a))₂)_(n1)S(O)_(n3)R^(d);(p.) —(C(R^(a))₂)_(n2)C(O)N(H)OR^(d); (q.) —(C(R^(a))₂)_(n1)CN; (r.)—C^(H) or —(C(R^(a))₂)_(n1)—C^(H); (s.) —C(R^(a))₂O—C^(C); and (t.)—C(O)CF₃; each R^(a) is independently H, C₁-C₃ alkyl, C₁-C₃ fluoroalkyl,or C₃-C₆ cycloalkyl, or alternatively two R^(a) when bonded to a commoncarbon atom may together with the common carbon atom form a cyclopropylring; each R^(b) is independently: (i.) H; (ii.) C₁-C₆ alkyl, whereinsaid C₁-C₆ alkyl is unsubstituted or independently substituted by 1 to 3fluoro, or hydroxyl; (iii.) —(CH₂)_(n3)CO₂R^(e); or (iv.) —C^(C) or—CH₂—C^(C); or alternatively, two R^(b) together with the N atom towhich they are attached form a 5- to 9-membered heterocyclyl, whereinsaid heterocyclyl is a saturated, partially saturated, or aromatic ringsystem containing 0, 1, or 2 additional heteroatoms independentlyselected from the group consisting of N, O, S, and S(O)₂; wherein saidheterocyclyl is unsubstituted or substituted by 1 to 4 moietiesindependently selected from the group consisting of C₁-C₆ alkyl, C₁-C₃alkoxy, fluoro, hydroxyl, oxo, cyano, amino, C₁-C₃ alkylamino, and C₁-C₃dialkylamino; R^(c) is (i.) H; (ii.) C₁-C₆ alkyl, wherein said C₁-C₆alkyl is unsubstituted or independently substituted by 1 to 3 fluoro orhydroxy; or (iii.) —C^(C) or CH₂—C^(C); R^(d) is (i.) C₁-C₆ alkyl,wherein said C₁-C₆ alkyl is unsubstituted or independently substitutedby 1 to 3 fluoro or hydroxy; (ii). —C(O)N(R^(f))₂; or (iii.) —C^(C) orCH₂—C^(C); R^(e) is H or C₁-C₃ alkyl; R^(f) is H or C₁-C₃ alkyl; ringC^(H) is (i.) C₃-C₆ cycloalkyl; (ii.) phenyl; or (iii.) a 4- to9-membered mono- or bicyclic heterocyclyl, wherein said heterocyclyl isa saturated, partially saturated, or aromatic ring system containing 1to 4 heteroatoms independently selected from the group consisting of N,O, S, and S(O)₂; wherein ring C^(H) is unsubstituted or independentlysubstituted by 1 to 4 C₁-C₆ alkyl, C₁-C₃ alkoxy, halo, hydroxyl, oxo,cyano, amino, C₁-C₃ alkylamino, or C₁-C₃ dialkylamino; ring C^(C) is(i.) C₃-C₆ cycloalkyl; (ii.) phenyl; or (iii.) a heterocyclyl of theformula

 wherein said heterocyclyl is a 5- to 9-membered heterocyclyl, whereinsaid heterocyclyl is a saturated, partially saturated, or aromatic ringsystem that contains 1, 2, or 3 heteroatoms independently selected fromthe group consisting of N, O, S, and S(O)₂; wherein ring C^(C) isunsubstituted or independently substituted by 1 to 4 C₁-C₆ alkyl, C₁-C₃alkoxy, halo, hydroxyl, oxo, cyano, amino, C₁-C₃ alkylamino, or C₁-C₃dialkylamino; the subscript n1 is 1, 2, or 3; the subscript n2 is 0, 1,2, or 3; the subscript n3 is 1 or 2; R⁴ is (a.) C₁-C₈ alkyl, whereinsaid C₁-C₈ alkyl of R⁴ is unsubstituted or independently substituted by1 to 6 halo, C₁-C₃ alkoxy, hydroxy, cyano, trimethylsilyl, ormethylsulfonyl; (b.) C₂-C₈ alkenyl, wherein said C₂-C₈ alkenyl of R⁴ isunsubstituted or independently substituted by 1 to 6 fluoro or cyano; or(c.) a group of the formula -M-R^(CH); M is (i.) a bond; or (ii.) C₁-C₆alkylene, wherein said C₁-C₆ alkylene of M is unsubstituted orsubstituted by 1 to 6 fluoro; R^(CH) is a ring selected from the groupconsisting of (i.) C₃-C₉ mono- or bicycloalkyl; (ii.) phenyl; and (iii.)a 3- to 6-membered heterocyclyl, wherein said heterocyclyl of R^(CH) isa saturated, partially saturated or aromatic ring system containing 1 to2 heteroatoms independently selected from the group consisting of N, O,and S; wherein R^(CH) is unsubstituted or independently substituted by 1to 4 halo, C₁-C₃ alkyl, C₁-C₃ trifluoroalkyl, cyano, C₁-C₄alkylcarbonylamino, or oxo; Cy is (a.) phenyl; (b.) C₃-C₆ cycloalkyl; or(c.) a 5- to 9-membered mono- or bicyclic heterocyclyl, wherein saidheterocyclyl of Cy is a saturated, partially saturated, or aromatic ringsystem containing 1 to 3 heteroatoms independently selected from thegroup consisting of N, O, S and S(O)₂; wherein Cy is unsubstituted orindependently substituted by 1 to 4 R^(k) moieties selected from thegroup consisting of: (i.) C₁-C₆ alkyl, wherein said C₁-C₆ alkyl isunsubstituted or independently substituted by 1 to 3 hydroxy or fluoro;(ii.) C₁-C₆ alkoxy, wherein said C₁-C₆ alkoxy is unsubstituted orindependently substituted by 1 to 3 fluoro, hydroxy, amino, (C₁-C₃alkyl)amino, di(C₁-C₃ alkyl)amino, methoxy, or phenyl; (iii.)—N(R^(e1))₂; (iv.) —O(CH₂)_(n4)C(O)N(R^(e1))₂; (v.)—O(CH₂)_(n5)CO₂R^(e1); (vi.) hydroxyl; (vii.) oxo; (viii.) halo; (ix.)C₁-C₃ alkylsulfonyl; (x.) cyano; (xi.) oxetanyl; and (xii.) cyclopropyl;or alternatively, two R^(k) moieties, when substituted on adjacent ringatoms of Cy, form a second ring, wherein said second ring is a 5- to7-membered saturated, partially saturated, or aromatic ring system thatcontains 0, 1, or 2 heteroatoms independently selected from the groupconsisting of N, O, and S; wherein said second ring is unsubstituted orsubstituted by 1 to 3 R^(k) moieties independently selected from(i)-(xi); each R^(e1) is independently H or C₁-C₃ alkyl; the subscriptn4 is 1, 2, or 3; and the subscript n5 is 1, 2, or
 3. 2. The compound ofclaim 1 or a pharmaceutically acceptable salt thereof, wherein R⁴ is agroup of the formula


3. The compound of claim 1 or a pharmaceutically acceptable saltthereof, wherein R¹ is H or methyl.
 4. The compound of claim 1 or apharmaceutically acceptable salt thereof, wherein Cy is a group of theformula, or

wherein the subscript s is 0, 1, 2, or
 3. 5. The compound of claim 1 ora pharmaceutically acceptable salt thereof, wherein R³ is a group of theformula —(C(R^(a))₂)_(n1)N(H)S(O)₂N(R^(b))₂.
 6. The compound of claim 5or a pharmaceutically acceptable salt thereof, wherein the subscript n1is
 1. 7. The compound of claim 6 or a pharmaceutically acceptable saltthereof, wherein each R^(b) is independently: (i.) H; (ii.) C₁-C₄ alkyl,wherein said C₁-C₄ alkyl is unsubstituted or substituted by 1 to 3fluoro; or (iii.) —C^(C); or alternatively, two R^(b) together with theN atom to which they are attached form a 5- to 6-membered heterocyclyl,wherein said heterocyclyl is selected from the group consisting ofpyrrolidinyl, piperidinyl, and morpholinyl; wherein said heterocyclyl isunsubstituted or substituted by 1 to 2 moieties independently selectedfrom the group consisting of C₁-C₆ alkyl, C₁-C₃ alkoxy, fluoro,hydroxyl, oxo, cyano, amino, C₁-C₃ alkylamino, and C₁-C₃ dialkylamino;and ring C^(C) is C₃-C₆ cycloalkyl; wherein ring C^(C) is unsubstitutedor independently substituted by 1 to 2 C₁-C₆ alkyl, C₁-C₃ alkoxy, halo,hydroxyl, oxo, cyano, amino, C₁-C₃ alkylamino, or C₁-C₃ dialkylamino. 8.The compound of claim 1 or a pharmaceutically acceptable salt thereof,wherein R¹ is H or methyl; R² is H; R³ is—(C(R^(a))₂)_(n1)N(H)S(O)₂N(R^(b))₂; R⁴ is a group of the formula

and Cy is a group of the formula

wherein the subscript s is 0, 1, 2, or
 3. 9. The compound of claim 8 ora pharmaceutically acceptable salt thereof, wherein each R^(b) isindependently: (i.) H; (ii.) C₁-C₄ alkyl, wherein said C₁-C₄ alkyl isunsubstituted or substituted by 1 to 3 fluoro; or (iii.) —C^(C); oralternatively, two R^(b) together with the N atom to which they areattached form a 5- to 6-membered heterocyclyl, wherein said heterocyclylis selected from the group consisting of pyrrolidinyl, piperidinyl, andmorpholinyl; wherein said heterocyclyl is unsubstituted or substitutedby 1 to 2 moieties independently selected from the group consisting ofC₁-C₆ alkyl, C₁-C₃ alkoxy, fluoro, hydroxyl, oxo, cyano, amino, C₁-C₃alkylamino, and C₁-C₃ dialkylamino; and ring C^(C) is C₃-C₆ cycloalkyl;wherein ring C^(C) is unsubstituted or independently substituted by 1 to2 C₁-C₆ alkyl, C₁-C₃ alkoxy, halo, hydroxyl, oxo, cyano, amino, C₁-C₃alkylamino, or C₁-C₃ dialkylamino.
 10. A pharmaceutical compositioncomprising a therapeutically effective amount of a compound of claim 1or a pharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 11. A method of treating a disease or conditionmediated by RORgammaT comprising administering a therapeuticallyeffective amount of a compound of claim 1 or a pharmaceuticallyacceptable salt thereof to a patient in need of such treatment, whereinthe disease or condition is multiple sclerosis, inflammatory boweldisease, Crohn's disease, ankylosing spondylitis, psoriasis, rheumatoidarthritis, asthma, osteoarthritis, Kawasaki disease, Hashimoto'sthyroiditis, or mucosal leishmaniasis.
 12. The method of claim 11,further comprising administering an additional therapeutic agent to thepatient.
 13. The method of claim 11, wherein the disease or condition ismultiple sclerosis, inflammatory bowel disease, Crohn's disease,ankylosing spondylitis, psoriasis, rheumatoid arthritis, or asthma. 14.The method of claim 11, wherein the disease or condition is ankylosingspondylitis or psoriasis.
 15. The method of claim 14, wherein thecompound is a compound of claim
 8. 16. A compound selected from thefollowing, or a pharmaceutically acceptable salt thereof: (R)-tert-butyl(2-(hydroxymethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-tert-butyl(4-((5-bromo-2-chloropyridin-3-yl)sulfonyl)-2-(hydroxymethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-4-((6-((tert-butoxycarbonyl)amino)-2-(hydroxymethyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)sulfonyl)-1-(difluoromethyl)-3-methyl-1H-pyrazol-2-e;[(R)-4-(3-chloro-benzenesulfonyl)-2-hydroxymethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamicacid tert-butyl ester; (R)-tert-butyl(4-((5-bromopyridin-3-yl)sulfonyl)-2-(hydroxymethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-tert-butyl(2-(hydroxymethyl)-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-tert-butyl(2-(hydroxymethyl)-4-((3-(methylsulfonyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-tert-butyl(4-((2-chloro-5-methylpyridin-3-yl)sulfonyl)-2-(hydroxymethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-tert-butyl(4-((3-cyanophenyl)sulfonyl)-2-(hydroxymethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-tert-butyl(2-(hydroxymethyl)-4-((5-methyl-2-oxo-1,2-dihydropyridin-3-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-tert-butyl(4-((4-fluorophenyl)sulfonyl)-2-(2-hydroxypropan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(4-((4-fluorophenyl)sulfonyl)-2-(2-hydroxypropan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R and S)-1,1,1-trifluoro-2-methylpropan-2-yl4-(3,4-difluorophenylsulfonyl)-2-(2,2,2-trifluoroacetyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-ylcarbamate;(R and S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2,2,2-trifluoroacetyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(aminomethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(((benzyloxy)carbonyl)aminomethyl)-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-2-((3-(tetrahydro-2H-pyran-4-yl)ureido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(((benzyloxy)carbonyl)aminomethyl)-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(((benzyloxy)carbonyl)aminomethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(((methoxy)carbonyl)aminomethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-((3-cyclopropylureido)methyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-((3-cyclobutylureido)methyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-((3-(tert-butyl)ureido)methyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-2-((3-isopropylureido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-2-((3-(thiophen-3-yl)ureido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-((3-ethylureido)methyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-((3-cyclohexylureido)methyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-4-fluorophenyl)sulfonyl)-2-((5-methyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-2-(((N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-2-((morpholine-4-sulfonamido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(((N,N-diethylsulfamoyl)amino)methyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(((N,N-dimethylsulfamoyl)amino)methyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-2-((piperidine-1-sulfonamido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-2-((pyrrolidine-1-sulfonamido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;1,1,1-trifluoro-2-methylpropan-2-yl((2S)-4-((4-fluorophenyl)sulfonyl)-2-((2-methylpiperidine-1-sulfonamido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;1,1,1-trifluoro-2-methylpropan-2-yl((2S)-2-((2,6-dimethylmorpholine-4-sulfonamido)methyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-2-((4-methylpiperidine-1-sulfonamido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;1,1,1-trifluoro-2-methylpropan-2-yl((2S)-4-((4-fluorophenyl)sulfonyl)-2-((2-methylmorpholine-4-sulfonamido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(((N-cyclopropyl-N-methylsulfamoyl)amino)methyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(((N-cyclopentyl-N-methylsulfamoyl)amino)methyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-2-(((N-methyl-N-(2,2,2-trifluoroethyl)sulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-4-fluorophenyl)sulfonyl)-2-(((N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-4-fluorophenyl)sulfonyl)-2-((piperidine-1-sulfonamido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;1,1,1-trifluoro-2-methylpropan-2-yl((2S)-4-((3-chloro-4-fluorophenyl)sulfonyl)-2-((2-methylpiperidine-1-sulfonamido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;1,1,1-trifluoro-2-methylpropan-2-yl((2S)-4-((3-chloro-4-fluorophenyl)sulfonyl)-2-((2-methylmorpholine-4-sulfonamido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-4-fluorophenyl)sulfonyl)-2-(((N-methyl-N-(2,2,2-trifluoroethyl)sulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-4-fluorophenyl)sulfonyl)-2-(((N-isobutyl-N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;1,1,1-trifluoro-2-methylpropan-2-yl((2S)-4-((3-chloro-4-fluorophenyl)sulfonyl)-2-((3-methylpyrrolidine-1-sulfonamido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-4-fluorophenyl)sulfonyl)-2-(((N-ethylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-4-fluorophenyl)sulfonyl)-2-(((N-isopropylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(((N-ethylsulfamoyl)amino)methyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-2-(((N-isopropylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(((N-(tert-butyl)sulfamoyl)amino)methyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3,4-difluorophenyl)sulfonyl)-2-(((N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-ethoxy-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(((N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((1-ethyl-3-methyl-1H-pyrazol-4-yl)sulfonyl)-2-(((N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(((N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-(2,2-difluoroethoxy)-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(((N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((1-(2,2-difluoroethyl)-3-ethoxy-1H-pyrazol-4-yl)sulfonyl)-2-(((N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-2-(((N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((2-methoxy-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)sulfonyl)-2-(((N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-tert-butyl(2-((pyridin-2-ylthio)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-tert-butyl(2-((cyclopentylthio)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-tert-butyl(2-((benzylthio)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-tert-butyl(2-((tert-butylthio)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-tert-butyl(2-(((4,5-dimethyl-1H-imidazol-2-yl)thio)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-tert-butyl (2-((phenylthio)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-tert-butyl(2-((methylthio)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-tert-butyl(2-((pyridin-2-ylsulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-tert-butyl(2-((tert-butylsulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-tert-butyl(2-(((4,5-dimethyl-1H-imidazol-2-yl)sulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-tert-butyl(2-((phenylsulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-tert-butyl(2-((cyclopentylsulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-tert-butyl(2-((benzylsulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-tert-butyl(2-((methylsulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-tert-butyl(2-((pyridin-2-ylsulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-tert-butyl(2-((N-cyclopropylsulfamoyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-tert-butyl(2-((N-(2,2,2-trifluoroethyl)sulfamoyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-tert-butyl(2-((morpholinosulfonyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-tert-butyl(2-((N-ethylsulfamoyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-tert-butyl(2-((N,N-dimethylsulfamoyl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;1,1,1-trifluoro-2-methylpropan-2-yl(S)-(4-((3-ethoxy-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;[(2S,3S and2R,3R)-4-(3-cyano-benzenesulfonyl)-2-hydroxymethyl-3-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamicacid 2,2-dimethyl-propyl ester; (S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-3-(hydroxymethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-3-(hydroxymethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;[(S)-4-(3-cyano-benzenesulfonyl)-2-(2,4-dioxo-oxazolidin-3-ylmethyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamicacid tert-butyl ester; (1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl((S)-4-((3-cyanophenyl)sulfonyl)-2-((2,4-dioxooxazolidin-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-neopentyl(4-((3-cyanophenyl)sulfonyl)-2-((2,4-dioxooxazolidin-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(1S,4R)-bicyclo[2.2.1]heptan-2-yl((S)-2-((2,4-dioxooxazolidin-3-yl)methyl)-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-((2,4-dioxooxazolidin-3-yl)methyl)-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-neopentyl(2-((2,4-dioxooxazolidin-3-yl)methyl)-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(tetrahydro-2H-pyran-2-yl)methyl((S)-2-((2,4-dioxooxazolidin-3-yl)methyl)-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(2S)-bicyclo[2.2.1]heptan-2-yl((S)-4-((3-cyanophenyl)sulfonyl)-2-((2,4-dioxooxazolidin-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(2S)-bicyclo[2.2.1]heptan-2-yl((S)-2-((2,4-dioxooxazolidin-3-yl)methyl)-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;[(S)-4-(3-cyano-benzenesulfonyl)-2-dimethylaminomethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamicacid tert-butyl ester;[(S)-4-(3-cyano-benzenesulfonyl)-2-dimethylaminomethyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamicacid 2,2-dimethyl-propyl ester; (1S,4R)-bicyclo[2.2.1]heptan-2-yl((S)-4-((3-cyanophenyl)sulfonyl)-2-((dimethylamino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(1S,2R,4R)-bicyclo[2.2.1]heptan-2-yl((S)-4-((3-cyanophenyl)sulfonyl)-2-((dimethylamino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-neopentyl(2-((dimethylamino)methyl)-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;bicyclo[2.2.1]heptan-2-yl((S)-2-((dimethylamino)methyl)-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(2S)-bicyclo[2.2.1]heptan-2-yl((S)-2-((dimethylamino)methyl)-4-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tetrahydro-2H-pyran-4-yl(4-((3-cyanophenyl)sulfonyl)-2-((dimethylamino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-methyl2-(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate;(S)-methyl2-(6-((tert-butoxycarbonyl)amino)-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate;(S)-methyl2-(6-((tert-butoxycarbonyl)amino)-4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate;(S)-methyl2-(6-((tert-butoxycarbonyl)amino)-4-((4-fluoro-3-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate;(R)-methyl2-(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate;(S)-methyl2-(4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetate;[(S)-6-tert-butoxycarbonylamino-4-(1-difluoromethyl-3-methyl-1H-pyrazole-4-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl]-aceticacid;(S)-2-(6-((tert-butoxycarbonyl)amino)-4-((4-fluoro-3-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)aceticacid;(S)-2-(6-((tert-butoxycarbonyl)amino)-4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)aceticacid;(S)-2-(6-((tert-butoxycarbonyl)amino)-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)aceticacid;(S)-2-(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)aceticacid;(S)-2-(6-((tert-butoxycarbonyl)amino)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)aceticacid;(S)-2-(4-((4-fluorophenyl)sulfonyl)-6-(((neopentyloxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)aceticacid;(S)-2-(6-((tert-butoxycarbonyl)amino)-4-((3-chlorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)aceticacid;(S)-2-(4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)aceticacid;(R)-6-((tert-butoxycarbonyl)amino)-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylicacid;(R)-6-((tert-butoxycarbonyl)amino)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylicacid;(R)-6-((tert-butoxycarbonyl)amino)-4-((4-fluoro-3-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylicacid;(R)-4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylicacid;(R)-6-((tert-butoxycarbonyl)amino)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylicacid;(R)-6-((tert-butoxycarbonyl)amino)-4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxylicacid;[(S)-2-(2-azetidin-1-yl-2-oxo-ethyl)-4-(1-difluoromethyl-3-methyl-1H-pyrazole-4-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamicacid tert-butyl ester;[(S)-2-(2-azetidin-1-yl-2-oxo-ethyl)-4-(1-difluoromethyl-3-methyl-1H-pyrazole-4-sulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-carbamicacid 1,2,2-trimethyl-propyl ester; (S)-tert-butyl(2-(2-amino-2-oxoethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-amino-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(4-((4-fluorophenyl)sulfonyl)-2-(2-(methylamino)-2-oxoethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-(methylamino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-(dimethylamino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;tert-butyl(2-(2-(dimethylamino)-2-oxoethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-tert-butyl(4-((3-chloro-4-fluorophenyl)sulfonyl)-2-(2-(methylamino)-2-oxoethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(4-((3-chloro-4-fluorophenyl)sulfonyl)-2-(2-(methylamino)-2-oxoethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-4-fluorophenyl)sulfonyl)-2-(2-(methylamino)-2-oxoethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-tert-butyl(2-(2-(oxazolidin-3-yl)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-((cyclobutylmethyl)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-oxo-2-((3,3,3-trifluoropropyl)amino)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-(isobutylamino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-(((1H-pyrazol-4-yl)methyl)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-(((1-methyl-1H-pyrazol-4-yl)methyl)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-(((1H-pyrazol-3-yl)methyl)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-(((1-isopropyl-1H-pyrazol-4-yl)methyl)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-oxo-2-((pyrazolo[1,5-a]pyridin-3-ylmethyl)amino)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-(((1-ethyl-1H-pyrazol-3-yl)methyl)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-(1-methylpyrrolo[3,4-c]pyrazol-5(1H,4H,6H)-yl)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-(((1-methyl-1H-pyrazol-3-yl)methyl)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-(((1-ethyl-1H-pyrazol-4-yl)methyl)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-(((1-ethyl-5-methyl-1H-pyrazol-4-yl)methyl)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-(((1,5-dimethyl-1H-pyrazol-4-yl)methyl)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate(S)-tert-butyl(2-(2-(((1-benzyl-1H-pyrazol-4-yl)methyl)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-3-(2-(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetamido)propanoicacid (S)-methyl3-(2-(6-((tert-butoxycarbonyl)amino)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetamido)propanoate;(S)-tert-butyl(2-(2-oxo-2-((4-(trifluoromethyl)benzyl)amino)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-(benzylamino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-((cyclopropylmethyl)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-oxo-2-(propylamino)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-(ethylamino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-(oxazolidin-3-yl)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-neopentyl(2-(2-(methylamino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-(((2H-tetrazol-5-yl)methyl)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-((2-hydroxyethyl)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-(tert-butylamino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;tert-butyl((2S)-2-(2-(2-methylazetidin-1-yl)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-(3-cyanoazetidin-1-yl)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-(3-methoxyazetidin-1-yl)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-(azetidin-1-yl)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-(azetidin-1-yl)-2-oxoethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-(3-methylazetidin-1-yl)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-neopentyl(2-(2-(azetidin-1-yl)-2-oxoethyl)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-tert-butyl(2-carbamoyl-4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-carbamoyl-4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-tert-butyl(2-carbamoyl-4-((4-fluoro-3-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-methyl3-(6-((tert-butoxycarbonyl)amino)-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamido)propanoate;(R)-tert-butyl(2-carbamoyl-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-tert-butyl(4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-2-(dimethylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-3-(6-((tert-butoxycarbonyl)amino)-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-2-carboxamido)propanoicacid; tert-butyl(2-(2-cyanopropan-2-yl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R and S)2-(4-((4-fluorophenyl)sulfonyl)-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)-2-methylpropanoicacid; (R and S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-2-(2-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)propan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-oxo-2-(trifluoromethylsulfonamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-neopentyl(2-(2-(cyclopropanesulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-neopentyl(4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-oxo-2-(trifluoromethylsulfonamido)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-oxo-2-(thiazole-2-sulfonamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-oxo-2-(pyridine-4-sulfonamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-(1,1-dimethylethylsulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-oxo-2-(5-(trifluoromethyl)pyridine-2-sulfonamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-neopentyl(4-((4-fluorophenyl)sulfonyl)-2-(2-oxo-2-(trifluoromethylsulfonamido)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-oxo-2-(pyridine-2-sulfonamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-oxo-2-(pyridine-3-sulfonamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-oxo-2-(4-(trifluoromethyl)pyridine-2-sulfonamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-oxo-2-(1H-pyrazole-4-sulfonamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-(4-methylpyridine-2-sulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-(2-fluoro-5-methylphenylsulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-(2-fluorophenylsulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-oxo-2-(2-(trifluoromethyl)phenylsulfonamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-oxo-2-(3-(trifluoromethyl)phenylsulfonamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-(3-fluorophenylsulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-(cyclopropanesulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-(4-methylphenylsulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-(1-methylethylsulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-(ethylsulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-(methylsulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-neopentyl(2-(2-(cyclopropanesulfonamido)-2-oxoethyl)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-(cyclopentanesulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-(2-methylphenylsulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-(4-fluorophenylsulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-(2,5-dimethylphenylsulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-oxo-2-(4-propylphenylsulfonamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-(6-methylpyridine-2-sulfonamido)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-neopentyl(2-(2-(cyclopropanesulfonamido)-2-oxoethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-(2-(2-(methoxyamino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamicacid; (S)-tert-butyl(2-(2-oxo-2-((2-(trifluoromethyl)phenoxy)amino)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-oxo-2-((pyridin-3-ylmethoxy)amino)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-oxo-2-(((4-(trifluoromethyl)benzyl)oxy)amino)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-oxo-2-(((3-(trifluoromethyl)benzyl)oxy)amino)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-((4-fluorophenoxy)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-((cyclopentyloxy)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-(ethoxyamino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-((benzyloxy)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-(((4-methylbenzyl)oxy)amino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-(isopropoxyamino)-2-oxoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-oxo-2-(propoxyamino)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-tert-butyl(4-((4-fluorophenyl)sulfonyl)-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-tert-butyl(4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-tert-butyl(4-((3-chloro-4-fluorophenyl)sulfonyl)-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-tert-butyl(4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(4-((4-fluorophenyl)sulfonyl)-2-((4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-2-((4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-((4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-tert-butyl(4-((4-fluorophenyl)sulfonyl)-2-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;tert-butyl(2-(cyanomethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;tert-butyl(2-(2-hydroxypropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-amino-2-methylpropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-acetamido-2-methylpropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-propionamidoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;tert-butyl((2S)-2-(2-(2-hydroxypropanamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-(oxetane-3-carboxamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-isobutyramidoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-acetamidoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-(cyclopropanecarboxamido)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(4-((4-fluorophenyl)sulfonyl)-2-(2-propionamidoethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-acetamidoethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;tert-butyl((2S)-4-((4-fluorophenyl)sulfonyl)-2-(2-(2-hydroxypropanamido)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-(cyclopropanecarboxamido)ethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-neopentyl(4-((4-fluorophenyl)sulfonyl)-2-(2-propionamidoethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-neopentyl(2-(2-acetamidoethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-neopentyl(2-(2-(cyclopropanecarboxamido)ethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-amino-2-methylpropyl)-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-amino-2-methylpropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-(2-oxopyrrolidin-1-yl)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-(2-oxopyrrolidin-1-yl)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-acetamido-2-methylpropyl)-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-acetamido-2-methylpropyl)-4-((3,4-difluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-acetamido-2-methylpropyl)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-acetamido-2-methylpropyl)-4-((1-(difluoromethyl)-5-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-acetamido-2-methylpropyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-tert-butyl(2-(2-acetamido-2-methylpropyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-acetamido-2-methylpropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-acetamido-2-methylpropyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-acetamido-2-methylpropyl)-4-((3-chloro-4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-acetamido-2-methylpropyl)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-2-(2-methyl-2-(methylsulfonamido)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-acetamido-2-methylpropyl)-4-((3,4-difluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-4-fluorophenyl)sulfonyl)-2-(2-methyl-2-(methylsulfonamido)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3,4-difluorophenyl)sulfonyl)-2-(2-methyl-2-(methylsulfonamido)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-(cyclopropanesulfonamido)-2-methylpropyl)-4-((3,4-difluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-methyl-2-(methylsulfonamido)propyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-(cyclopropanesulfonamido)-2-methylpropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-4-fluorophenyl)sulfonyl)-2-(2-methyl-2-(methylsulfonamido)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-(cyclopropanesulfonamido)-2-methylpropyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-(cyclopropanesulfonamido)-2-methylpropyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-methyl-2-(trifluoromethylsulfonamido)propyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-(2-(dimethylamino)-2-oxoacetamido)-2-methylpropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-acetamido-2-methylpropyl)-4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-acetamido-2-methylpropyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-acetamido-2-methylpropyl)-4-((3-methoxy-1,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-acetamido-2-methylpropyl)-4-((1-(difluoromethyl)-3-ethoxy-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-acetamido-2-methylpropyl)-4-((3-(difluoromethoxy)-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;tert-butyl(2-(2-hydroxyethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;tert-butyl(2-((1H-imidazol-2-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;tert-butyl(2-((1-methyl-1H-imidazol-2-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(4-((4-fluorophenyl)sulfonyl)-2-((2-oxopyrrolidin-1-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-((1H-pyrazol-1-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-((2H-1,2,3-triazol-2-yl)methyl)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-((4H-1,2,4-triazol-4-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-((1H-1,2,4-triazol-1-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-((1H-1,2,3-triazol-1-yl)methyl)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-((1H-1,2,3-triazol-1-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-((2H-1,2,3-triazol-2-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-tert-butyl(2-((pyridin-2-yloxy)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl (2-((2-oxopyridin-1(2H)-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-((5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;tert-butyl(2-(2-hydroxy-2-methylpropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-((3-hydroxyazetidin-1-yl)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(((3-methyloxetan-3-yl)amino)methyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;tert-butyl((2S)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-2-(((1,1,1-trifluoropropan-2-yl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;1,1,1-trifluoro-2-methylpropan-2-yl((2S)-4-((4-fluorophenyl)sulfonyl)-2-((2-methylazetidin-1-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-2-((3-hydroxyazetidin-1-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(azetidin-1-ylmethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-2-(2,2,2-trifluoroacetyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;2,2,2-trifluoro-1,1-dimethylethyl[(2S)-4-{[1-(difluoromethyl)-3-(2-hydroxyethoxy)-1H-pyrazol-4-yl]sulfonyl}-2-{[(methylsulfamoyl)amino]methyl}-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbamate;2,2,2-trifluoro-1,1-dimethylethyl[(2S)-2-[2-(acetylamino)-2-methylpropyl]-4-{[1-ethyl-3-(2-hydroxyethoxy)-1H-pyrazol-4-yl]sulfonyl}-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbamate;1,1,1-trifluoro-2-methylpropan-2-yl((R)-4-((3,4-difluorophenyl)sulfonyl)-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;1,1,1-trifluoro-2-methylpropan-2-yl((S)-4-((3,4-difluorophenyl)sulfonyl)-2-((R)-2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;1,1,1-trifluoro-2-methylpropan-2-yl((R)-4-((3,4-difluorophenyl)sulfonyl)-2-((R)-2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;1,1,1-trifluoro-2-methylpropan-2-yl((S)-4-((3,4-difluorophenyl)sulfonyl)-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;1,1,1-trifluoro-2-methylpropan-2-yl((R)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;1,1,1-trifluoro-2-methylpropan-2-yl((R)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-((R)-2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;1,1,1-trifluoro-2-methylpropan-2-yl((S)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-((S)-2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;1,1,1-trifluoro-2-methylpropan-2-yl((R)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-((R)-2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluorophenyl)sulfonyl)-2-(2,2,2-trifluoro-1-hydroxyethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;1,1,1-trifluoro-2-methylpropan-2-yl((S)-2-((R)-1-amino-2,2,2-trifluoroethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;1,1,1-trifluoro-2-methylpropan-2-yl((S)-2-((S)-1-amino-2,2,2-trifluoroethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;1,1,1-trifluoro-2-methylpropan-2-yl((R)-2-((R)-1-amino-2,2,2-trifluoroethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;1,1,1-trifluoro-2-methylpropan-2-yl((R)-2-((S)-1-amino-2,2,2-trifluoroethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(2-(2-(ethylsulfonyl)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-(ethylsulfonyl)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;1,1,1-trifluoro-2-methylpropan-2-yl((2S,3R)-4-((1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl)sulfonyl)-3-methyl-2-(((N-methylsulfamoyl)amino)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;1,1,1-trifluoro-2-methylpropan-2-ylN-[(2S,3R)-2-[(1S)-1-S[[(benzyloxy)carbonyl]amino]ethyl]-4-[(3,4-difluorobenzene)sulfonyl]-3-methyl-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbamate;1,1,1-trifluoro-2-methylpropan-2-yl(3-(acetamidomethyl)-4-((4-fluorophenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-((1-carbamoylcyclopropyl)methyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-((1-carbamoylcyclopropyl)methyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;1,1,1-trifluoro-2-methylpropan-2-yl((S)-2-((R)-3-amino-2-cyclopropyl-3-oxopropyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;1,1,1-trifluoro-2-methylpropan-2-yl((S)-2-((S)-3-amino-2-cyclopropyl-3-oxopropyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(3-amino-2,2-dimethyl-3-oxopropyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(3-amino-2,2-dimethyl-3-oxopropyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(3-amino-2,2-dimethyl-3-oxopropyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(3-amino-2,2-dimethyl-3-oxopropyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;2,2,2-trifluoro-1,1-dimethylethyl{(2S)-2-(3-amino-2,2-dimethyl-3-oxopropyl)-4-[(4-fluoro-3-methoxyphenyl)sulfonyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbamate;1,1,1-trifluoro-2-methylpropan-2-yl((S)-2-((S)-3-amino-2-cyclopropyl-3-oxopropyl)-4-((4-fluoro-3-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;1,1,1-trifluoro-2-methylpropan-2-yl((S)-2-((S)-3-amino-2-cyclopropyl-3-oxopropyl)-4-((3-ethoxy-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;1,1,1-trifluoro-2-methylpropan-2-yl((S)-2-((R)-3-amino-2-cyclopropyl-3-oxopropyl)-4-((4-fluoro-3-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;1,1,1-trifluoro-2-methylpropan-2-yl((S)-2-((R)-3-amino-2-cyclopropyl-3-oxopropyl)-4-((3-ethoxy-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;2,2,2-trifluoro-1,1-dimethylethyl[(2S)-2-(3-amino-2,2-dimethyl-3-oxopropyl)-4-{[5-(trifluoromethyl)pyridin-3-yl]sulfonyl}-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbamate;2,2,2-trifluoro-1,1-dimethylethyl{2-(3-amino-2,2-dimethyl-3-oxopropyl)-4-[(3-ethoxy-1-ethyl-1H-pyrazol-4-yl)sulfonyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbamate;2,2,2-trifluoro-1,1-dimethylethyl[2-(3-amino-2,2-dimethyl-3-oxopropyl)-4-{[1-ethyl-3-(2-hydroxyethoxy)-1H-pyrazol-4-yl]sulfonyl}-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbamate;(S)-methyl2-((4-((2-(3-amino-2,2-dimethyl-3-oxopropyl)-6-((((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)amino)-2H-benzo[b][1,4]oxazin-4(3H)-yl)sulfonyl)-1-ethyl-1H-pyrazol-3-yl)oxy)acetate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-cyanoethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-((1-cyanocyclopropyl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-((1-cyanocyclopropyl)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-cyano-2-methylpropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-cyano-2-methylpropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-cyano-2-methylpropyl)-4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-cyano-2-methylpropyl)-4-((4-fluoro-3-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-cyano-2-methylpropyl)-4-((4-fluoro-3-methylphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-cyano-2-methylpropyl)-4-((4-fluoro-3-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-cyano-2-methylpropyl)-4-((4-fluoro-3-methylphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-cyano-2-methylpropyl)-4-((3-ethoxy-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-cyano-2-methylpropyl)-4-((3-ethoxy-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(3-(cyclopropanesulfonamido)-3-oxopropyl)-4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;1,1,1-trifluoro-2-methylpropan-2-yl((S)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-((S)-3-(cyclopropanesulfonamido)-2-methyl-3-oxopropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;1,1,1-trifluoro-2-methylpropan-2-yl((S)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-((R)-3-(cyclopropanesulfonamido)-2-methyl-3-oxopropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;2,2,2-trifluoro-1,1-dimethylethyl[(2S)-2-{3-[(tert-butylsulfonyl)amino]-3-oxopropyl}-4-{[4-fluoro-3-(trifluoromethyl)phenyl]sulfonyl}-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbamate;2,2,2-trifluoro-1,1-dimethylethyl[(2S)-4-{[4-fluoro-3-(trifluoromethyl)phenyl]sulfonyl}-2-(3-{[(4-methylphenyl)sulfonyl]amino}-3-oxopropyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbamate;2,2,2-trifluoro-1,1-dimethylethyl[(2S)-4-{[4-fluoro-3-(trifluoromethyl)phenyl]sulfonyl}-2-(3-oxo-3-{[(trifluoromethyl)sulfonyl]amino}propyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbamate;1,1,1-trifluoro-2-methylpropan-2-yl ((S)-2-((R andS)-3-(cyclopropanesulfonamido)-2-methyl-3-oxopropyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;1,1,1-trifluoro-2-methylpropan-2-yl((S)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-((R)-3-(1,1-dimethylethylsulfonamido)-2-methyl-3-oxopropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;1,1,1-trifluoro-2-methylpropan-2-yl((S)-2-((R)-3-(cyclopropanesulfonamido)-2-methyl-3-oxopropyl)-4-((4-fluoro-3-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;1,1,1-trifluoro-2-methylpropan-2-yl((S)-2-((R)-3-(1,1-dimethylethylsulfonamido)-2-methyl-3-oxopropyl)-4-((4-fluoro-3-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;1,1,1-trifluoro-2-methylpropan-2-yl((S)-2-((S)-3-(cyclopropanesulfonamido)-2-methyl-3-oxopropyl)-4-((4-fluoro-3-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;1,1,1-trifluoro-2-methylpropan-2-yl((S)-2-((S)-3-(1,1-dimethylethylsulfonamido)-2-methyl-3-oxopropyl)-4-((4-fluoro-3-methoxyphenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;1,1,1-trifluoro-2-methylpropan-2-yl((S)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-((S)-3-(1,1-dimethylethylsulfonamido)-2-methyl-3-oxopropyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluoro-3-(trifluoromethyl)phenyl)sulfonyl)-2-(oxetan-3-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-(4-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-methyl-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-methyl-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;2,2,2-trifluoro-1,1-dimethylethyl[(2S)-2-[2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethyl]-4-{[3-(trifluoromethyl)phenyl]sulfonyl}-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbamate;2,2,2-trifluoro-1,1-dimethylethyl{(2S)-4-[(3-cyclopropylphenyl)sulfonyl]-2-[2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbamate;tert-butyl{(2S)-4-[(3-cyclopropylphenyl)sulfonyl]-2-[2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-tert-butyl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-methyl-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluoro-3-methoxyphenyl)sulfonyl)-2-(2-methyl-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-methyl-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((4-fluoro-3-methoxyphenyl)sulfonyl)-2-(2-methyl-2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)ethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-2-(2-methyl-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;2,2,2-trifluoro-1,1-dimethylethyl {(2S)-4-[(3-cyclopropylphenyl)sulfonyl]-2-[2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbamate;2,2,2-trifluoro-1,1-dimethylethyl{(2S)-4-[(4-fluoro-3-methoxyphenyl)sulfonyl]-2-[2-methyl-2-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-(1H-tetrazol-5-yl)ethyl)-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;2,2,2-trifluoro-1,1-dimethylethyl {(2S)-4-[(3-cyclopropylphenyl)sulfonyl]-2-[2-(1H-tetrazol-5-yl)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbamate;2,2,2-trifluoro-1,1-dimethylethyl[(2S)-2-[2-(1H-tetrazol-5-yl)ethyl]-4-{[2-(trifluoromethyl)pyridin-4-yl]sulfonyl}-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbamate;(S)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(2-(1H-tetrazol-5-yl)ethyl)-4-((3-chloro-1-ethyl-1H-pyrazol-4-yl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;(R)-1,1,1-trifluoro-2-methylpropan-2-yl(2-(hydroxymethyl)-5-methyl-4-((3-(trifluoromethyl)phenyl)sulfonyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate;and (S)-tert-butyl(4-((4-fluorophenyl)sulfonyl)-2-((3-methylureido)methyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)carbamate.